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SPECIAL ARTICLE

The functional matrix hypothesis revisited. 1. The role
of mechanotransduction
           Melvin L. Moss, DDS, PhD
           New York, N.Y.

           The periodic incorporation of advances in the biomedical, bioengineering, and computer
           sciences allow the creation of increasingly more comprehensive revisions of the functional
           matrix hypothesis. Inclusion of two topics, (1) the mechanisms of cellular mechanotransduction,
           and (2) biologic network theory, permit this latest revision; presented here in two interrelated
           articles. In this first article, the several possible types of intracellular processes of
           mechanotransduction are described. These translate the informational content of a periosteal
           functional matrix stimulus into a skeletal unit (bone) cell signal. The correlation between the
           strengths of the endogenous electrical fields produced by muscle skeletal muscle activity, and
           those to which bone cells maximally respond are stressed. Further, a physical chain of
           macromolecular levers, connecting the extracellular matrix to the bone cell genome is
           described, suggesting another means of epigenetic regulation of the bone cell genome,
           including its phenotypic expression. (Am J Orthod Dentofac Orthop 1997;112:8-11 .)


    Introduction. This series of four articles is a                      functional matrix over the years. This is the one
cohesive and constructive perspective of "where we                       that will be referred to for decades to come, and
are now after all the dust has settled." But, there is                   the one graduate students now will discuss in their
another important and I think key feature and that                       seminars.
is a discussion of functional matrix-type studies (by                        One point I would have liked Dr. Moss to have
different names, perhaps) in other biologic disciplines                  addressed in greater depth in the final pages is how
that otherwise we probably would be quite unaware of                     the functional matrix is involved in its own growth
This in itself is a most noteworthy contribution,                        and development on how it is controlled. That is,
because most of us, in both the basic and clinical                       how much genome and how do the provocative
orthodontic sciences, are really not aware of ad-                        ideas of complexity and self-organization play into
vances in other relevant fields. We can learn! Then,                     this?
at the end, there is a look at the future, and this goes                                                       Donald Enlow
conceptually beyond anything we presume to under-
stand today. In all, Dr. Moss's assessment of his own                             T h i s article is presented as a series of
work as a revision is, I think, more of a scholarly                      interrelated articles, of which this is the first. The
elaboration, based on a broad quiltword of biologic                      second article contains both a comprehensive sum-
understanding, now gleaned from a variety of other                       mary of this latest revision of the F M H as well as the
specialties.                                                             reference list for both articles.
    There surely is room in our distinguished jour-
nal, which has a solid reputation for recognizing                        DEVELOPMENT OF THE FUNCTIONAL MATRIX
balance, for an introspective dissection of a biologic                   HYPOTHESIS (FMH)
concept that has profound clinical meaning. When                             A decade's study of the regulatory roles of
that concept is evaluated in the light of parallel
                                                                         intrinsic (genomic) and extrinsic (epigenetic) factors
biologic theory, uncovered from other diverse fields,
it presents a perspective for orthodontic scholars                       in cephalic growth evolved into the functional ma-
available nowhere else.                                                  trix hypothesis (FMH). 1 This initial version, as aug-
    There are countless Moss references on the                           mented, 2 and stressing epigenetic primacy (as de-
                                                                         fined in Moss 3 and Herring4), became peer-accepted
From the Department of Anatomy and Cell Biology, College of Physicians   as one explanatory paradigm.
and Surgeons, and School of Dental and Oral Surgery, Columbia Univer-
sity.                                                                        Periodically, incorporation of advances in the
Reprint requests to: Prof. Emeritus Melvin L. Moss, Department of        biomedical, bioengineering, and computer sciences
Anatomy and Cell Biology, Columbia University, 630 W. 168th St., New     have created more comprehensively explanatory
York, NY 10032. e-mail: moss@cucersl.civil.columbia.edu
Copyright © 1997 by the American Association of Orthodontists.           F M H versions. 5,6 And recent work on two topics,
0889-5406/97/$5.00 + 0 8/1/70662                                         cellular transduction of informational signals and
8
American Journal of Orthodontics and Dentofacial Orthopedics                                                 Moss   9
Volume 112, No. 1


biologic cellular network theory, permit the presen-           cephalic growth, at the gross anatomic level, and it
tation of this latest revision. 7-1°                           had two explanatory constraints: methodologic and
                                                               hierarchical.
THE CONCEPTUAL AND A N A T O M I C BASES OF                        1. Methodologic constraint. Macroscopic mea-
THE REVISED FMH
                                                               surements, which use the techniques of point
    A comprehensible revision of the FMH should                mechanics and arbitrary reference frames, e.g.,
indicate (a) those portions that are retained, ex-             roentgenographic cephalometry, permitted only
tended or discarded, and (b) which prior deficien-             method-specific descriptions that cannot be struc-
cies are now resolved.                                         turally detailed. This constraint was removed by
    Although the principal FMH concepts are either             the continuum mechanics techniques of the finite
generally known or easily available, 1'11-18 three are         element method (FEM) 6'1921 and of the related
of particular resonance for this revision.                     macro and boundary element methods. 9,22
    The developmental origin of all cranial skeletal               This penultimate FEM revision added objective,
elements (e.g., skeletal units) and all their subsequent       reference-frame-invariant, fine-grained, and con-
changes in size and shape (e.g., form) and location, as        ceptually integrated descriptions of the quantitative
well as their maintenance in being, are always, without        aspects of localized cephalic growth kinematics to
exception, secondary, compensatory, and mechanically           the earlier qualitative (phenomenologic) descrip-
obligatory responses to the temporally and operation-          tions of growth dynamics. 4,6,9
ally prior demands of their related cephalic nonskel-              2. Hierarchical constraint. However, even that
etal cells, tissues, organs, and operational volumes           version's descriptions did not extend "downward" to
(e.g., the functional matrices).                               processes at the cellular, subcellular, or molecular
    More precisely, the FMH claims that epigenetic,            structural domains, or extend "upwards" to the
extraskeletal factors and processes are the prior,             multicellular processes by which bone tissues re-
proximate, extrinsic, and primary cause of all adap-           spond to lower level signals. All prior FMH versions
tive, secondary responses of skeletal tissues and              were "suspended" or "sandwiched" as it were, be-
organs? It follows that the responses of the skeletal          tween these two hierarchical levels.
unit (bone and cartilage) cells and tissues are not                Explicitly, the FMH could not describe either
directly regulated by informational content of the             how extrinsic, epigenetic FM stimuli are transduced
intrinsic skeletal cell genome per se. Rather, this            into regulatory signals by individual bone cells, or
additional, extrinsic, epigenetic information is cre-          how individual cells communicate to produce coor-
ated by functional matrix operations.                          dinated multicellular responses.
    The F M H postulates two types of functional                   At the lower cellular or molecular levels, another
matrices: periosteal and capsularJ 6'17 The former,            problem exists. Almost uniformly, experimental and
typified by skeletal muscles, regulates the histologi-         theoretical studies of bone adaptation consider only
cally observable active growth processes of skeletal           the unicellular, unimolecular, or unigenomic levels.
tissue adaptation.                                             Accordingly, their results and derivative hypotheses
    This new version deals only with the responses to          generally are not extensible to higher multicellular,
periosteal matrices. It now includes the molecular and         tissue, levels.
cellular processes underlying the triad of active skele-           Consequently, in prior FMH versions, significant
tal growth processes: deposition, resorption, and main-        disjunctions exist between the descriptions at each
tenance. Histologic studies of actively adapting osse-         of the several levels of bone organization. Such a
ous tissues demonstrate that (1) adjacent adaptational         hiatus is implicit in hierarchical theory in which the
tissue surfaces simultaneously show deposition, re-            attributes of successively higher levels are not simply
sorption, and maintenance; (2) adaptation is a tissue          the sum of lower level attributes. Rather, at each
process. Deposition and maintenance are functions of           higher level, new and more complex structural and
relatively large groups (cohorts, compartments) of             operational attributes arise that cannot be pre-
homologous osteoblasts, never single cells; and (3) a          dicted, even from a complete knowledge of those of
sharp demarcation exists between adjacent cohorts of           the lower levels23; e.g., the sum of all lower at-
active, depository, and quiescent (resting) osteoblasts.       tributes (biophysical, biochemical, genomic) of a
                                                               bone cell cannot predict the higher attributes of a
Constraints of the FMH
                                                               bone tissue.
    Initially, the FMH ~,2 provided only qualitative               At present, no unitary hypothesis provides a
narrative descriptions of the biologic dynamics of             comprehensive, coherent and integrated description
10 Moss                                                            American Journal of Orthodontics and Dentofacial Orthopedics
                                                                                                                      July 1997


of all the processes and mechanisms involved in            generally evoke one; (3) osseous signal transmission
bone growth, remodeling, adaptation, and mainte-           is aneural, whereas all other mechanosensational
nance at all structural levels. This newest FMH            signals use some afferent neural pathways28.41; and,
version, presented herein, transcends some hierar-         (4) the evoked bone adaptational responses are
chical constraints and permits seamless descriptions       confined within each "bone organ" independently,
at, and between, the several levels of bone structure      e.g., within a femur, so there is no necessary "inter-
and operation-from the genomic to the organ level.        bone" or organismal involvement.
It does so by the inclusion of two complementary               This process translates the information content
concepts: (1) that mechanotransduction occurs in           of a periosteal functional matrix stimulus into a
single bone cells, and (2) that bone cells are com-        skeletal unit cell signal, for example, it moves infor-
putational elements that function multicellularly as      mation hierarchically downward to the osteocytes.
a connected cellular network.                             There are two, possibly complementary, skeletal
    It is useful to present the database and derivative   cellular mechanotransductive processes: ionic and
theories, supportive of the inclusion of these two        mechanical.
concepts individually in a series of two coordinated           Ionic or electrical processes. This involves some
articles: the first on mechanotransduction and the        process(es) of ionic transport through the bone cell
second on connected cellular networks.                     (osteocytic) plasma membrane. There is a subse-
                                                          quent intercellular transmission of the created ionic
Mechanotransduction
                                                          or electrical signals that, in turn, are computed by
    All vital ceils are "irritable" or perturbed by and   the operation of an osseous connected cellular
respond to alterations in their external environment.     network (CCN), as described in the second article in
Mechanosensing processes enable a cell to sense           this series. That network's output regulates the
and to respond to extrinsic loadings, a widespread        multicellular bone cell responses. 1°,42
biologic attribute, 24-32 by using the processes of            Although no consensual agreement exists, osteo-
mechanoreception and of mechanotransduction.              cytic, ionic-mechanotransduction may involve sev-
The former transmits an extracellular physical stim-      eral, possibly parallel, cellular processes.
ulus into a receptor cell; the latter transduces or            Stretch-activated channels. Several types of defor-
transforms the stimulus's energetic and/or informa-       mation may occur in strained bone tissue. One of
tional content into an intracellular signal. Mechano-     these involves the plasma membrane stretch-acti-
transduction33 is one type of cellular signal transduc-   vated (S-A) ion channels, a structure found in bone
tion. 34-36 There are several mechanotransductive         cells, 43-46 in many other cell types,25 and significantly
processes, for example, mechanoelectrical and             in fibroblasts. 4v When activated in strained osteo-
mechanochemical. Whichever are used, bone adap-           cytes, they permit passage of a certain sized ion or
tation requires the subsequent intercellular trans-       set of ions, including K +, Ca 2+, Na +, and CS+. 46'48-50
mission of the transduced signals.                             Such ionic flow may, in turn, initiate intracellular
                                                          electrical events, for example, bone cell S-A chan-
Osseous Mechanotransduetion
                                                          nels may modulate membrane potential as well as
    Static37 and dynamic3s loadings are continuously      Ca 2+ ion fluxY ,5~ Other bone cell mechanically
applied to bone tissues, tending to deform both           stimulatory processes have been suggested.52
extracellular matrix and bone cells. When an appro-            Rough estimates of osteocytic mechanoreceptor
priate stimulus parameter exceeds threshold values,       strain sensitivity have been made, 1°,53 and the calcu-
the loaded tissue responds by the triad of bone cell      lated values cover the morphogenetically significant
adaptation processes. Both osteocytes and osteo-          strain range of 1000 to 3000 txe in the literature. 54-56
blasts are competent for intracellular stimulus re-           Electrical processes. These include several, non-
ception and transduction and for subsequent inter-        exclusive mechanotransductive processes (e.g., elec-
cellular signal transmission. Osteoblasts directly        tromechanical and electrokinetic), involving the
regulate bone deposition and maintenance and in-          plasma membrane and extracellular fluids. Electric
directly regulate osteoclastic resorption. 39,4°          field strength may also be a significant parameterF
    Osseous mechanotransduction is unique in four
ways: (1) Most other mechanosensory cells are                 1. Electromechanical. As in most cells, the osteo-
cytologically specialized, but bone cells are not; (2)           cytic plasma membrane contains voltage-acti-
one bone-loading stimulus can evoke three adapta-                vated ion channels, and transmembrane ion
tional responses, whereas nonosseous processes                   flow may be a significant osseous mechano-
American Journal of Orthodontics and Dentofacial Orthopedics                                                         Moss    11
Volume 112, No. 1


        transductive p r o c e s s . 58'59'6°-62 It is also possi-   alternative means by which periosteal functional
        ble that such ionic flows generate osteocytic                matrix activity may regulate hierarchically lower
        action potentials capable of transmission                    level bone cell genomic functions.
        through gap junctions. 63                                        The mechanical properties of the extracellular
     2. Electrokinetic. Bound and unbound electric                   matrix influence cell behavior. 71 Loaded mineral-
        charges exist in bone tissue, many associated                ized bone matrix tissue is deformed or strained.
        with the bone fluid(s) in the several osseous                Recent data indicate that a series of extracellular
        spaces or compartments. 42,64 It is generally                macromolecular mechanical levers exist, capable of
        agreed that electrical effects in fluid-filled               transmitting information from the strained matrix to
        bone are not piezoelectric, but rather of elec-              the bone cell nuclear membrane.
        trokinetic, that is, streaming potential (SP)                    The basis of this mechanism is the physical
        origin. 42'65'66 The SP is a measure of the                  continuity of the transmembrane molecule integrin.
        strain-generated potential (SGP) of con-                     This molecule is connected extracellularly with the
        vected electric charges in the fluid flow of                 macromolecular collagen of the organic matrix and
        deformed bone. The usually observed SPG of                   intracellularly with the cytoskekeletal actin. The
        +2 mV can initiate both osteogenesis and                     molecules of the latter, in turn, are connected to the
        osteocytic action potentials. 66'67                          nuclear membrane, at which site the action of the
     3. Electric field strength. Bone responds to exog-              mechanical lever chain previously noted initiates a
        enous electrical fields. 68 Although the extrin-             subsequent series of intranuclear processes regula-
        sic electrical parameter is unclear, field                   tory of genomic activity. 72-75 (See Shapiro et al., 76 for
        strength may play an important role. 69 A                    vimentin, and Green 77 for a general discussion of
        significant parallel exists between the param-               biophysical transductions.)
        eters of these exogenous electrical fields 68,69
                                                                         It is suggested that such a cytoskeletal lever
        and the endogenous fields produced by mus-                   chain, connecting to the nuclear membrane, can
        cle activity. Bone responds to exogenous elec-               provide a physical stimulus able to activate the
        trical fields in an effective range of 1 to 10               osteocytic genome, 78 possibly by first stimulating the
        ixV/cm, strengths that are "...on the order of
                                                                     activity of such components as the cfos
        those endogenously produced in bone tissue                   genes.36,73, 78-86
        during normal (muscle) activity "7° (italics
                                                                         It is by such an interconnected physical chain of
        mine).
                                                                     molecular levers that periosteal functional matrix
    Mechanical processes. Although it is probable                    activity may regulate the genomic activity of its
that the intracellular, transductive process discussed               strained skeletal unit bone cells, including their
later does not initiate action potentials, it is an                  phenotypic expression.
The functional matrix hypothesis revisited. 2. The role
of an osseous connected cellular network

           Melvin L. Moss, DDS, PhD
           New York, N.Y..

           Intercellular gap junctions permiz bone cells to intercellularly transmit, and subsequently process,
           periosteal functional matrix information, after its initial intraceilular mechanotransduction. In
           addition, gap junctions, as electrical synapses, underlie the organization of bone tissue as a
           connected cellular network, and the fact that all bone adaptation processes are multicellular. The
           structural and operational characteristics of such biologic networks are outlined and their specific
           bone cell attributes described. Specifically, bone is "tuned" to the precise frequencies of skeletal
           muscle activity. The inclusion of the concepts and databases that are related to the intracellular and
           intercellular bone cell mechanisms and processes of mechanotransduction and the organization of
           bone as a biologic connected cellular network permit revision of the functional matrix hypothesis,
           which offers an explanatory chain, extending from the epigenetic event of muscle contraction
           hierarchically downward to the regulation of the bone cell genome. (Am J Orthod Dentofac Orthop
           1997;112:221-6.)



         T h e first article in this series considered                    processes meet. 93 In compact bone, the canaliculi
the implications for the functional matrix hypothesis                     cross "cement lines," and they form extensive com-
(FMH) of the ability of bone cells to carry out                           munications between osteons and interstitial re-
intracellular mechanosensation and transduction                           gions. 94 Gap junctions also connect superficial os-
and intercellular communication. In this article, we                      teocytes to periosteal and endOsteal osteoblasts. All
will consider the implications for the FMH of the
                                                                          osteoblasts are similarly interconnected laterally.
inclusion of connectionist network theory.
                                                                          Vertically, gap junctions connect periosteal osteo-
                                                                          blasts with preosteoblastic cells, and these, in turn,
BONE AS AN OSSEOUS CONNECTED CELLULAR                                     are similarly interconnectedY Effectively, each
NETWORK (CCN)                                                             CCN is a true syncytium. 87,91,93Bone cells are elec-
       All bone cells, except osteoclasts, are extensively                trically active. 57,Ss,sS,95-ml In a very real sense, bone
interconnected by gap junctions 8791 that form an                         tissue is "hard-wired. ''7,s,96
o s s e o u s C C N . 7,8,42 In these junctions, connexin 43 is                In addition to permitting the intercellular trans-
the major protein. 92 Each osteocyte, enclosed within                     mission of ions and small molecules, gap junctions
its mineralized lacuna, has many (n = +80) cyto-                          exhibit both electrical and fluorescent dye transmis-
plasmic (canalicular) processes, _+15 ~m long and                         sion. 63 Gap junctions are electrical synapses, in
arrayed three-dimensionally, that interconnect with                       contradistinction to interneuronal, chemical syn-
similar processes of up to 12 neighboring cells.                          apses, and, significantly, they permit bidirectional
These processes lie within mineralized bone matrix                        signal traffic, e.g., biochemical, ionic.
channels (canaliculi). The small space between the                             Mechanotransductively activated bone cells, e.g.,
cell process plasma membrane and the canaticular                          osteocytes, can initiate membrane action potentials
wall is filled macromolecular complexes.                                  capable of transmission through interconnecting gap
       Gap junctions are found where the plasma mem-                      junctions. The primacy of ionic signals rather than
branes of a pair of markedly overlapping canalicular                      secondary messengers is suggested here, because,
                                                                          although bone cell transduction may also produce
From the Department of Anatomy and Cell Biology, Co]lege of Physicians
and Surgeons, and School of Dental and Oral Surgery, Columbia Univer-
                                                                          small biochemical molecules that can pass through
sity.                                                                     gap junctions, the time-course of mechanosensory
Reprint requests to: Prof. Emeritus Melvin L. Moss, Department of         processes is believed to be too rapid for the involve-
Anatomy and Cell Biology, 630 W. 168th St., New York, NY 10032. e-mail:
moss@cucersl.civil.columbia.edu
                                                                          ment of secondary messengersY. 32 (See Carvalho et
Copyright © 1997 by the American Association of Orthodontists.            al. 1°2 for an opposite view.) A CCN is operationally
0889-5406/97/$5.00 + 0 8/1/70663                                          analogous to an "artificial neural network," in which
                                                                                                                                221
222   Moss                                                            American Journal of Orthodontics and Dentofacial Orthopedics
                                                                                                                      August 1997

 massively parallel or parallel-distributed signal pro-       sentation of CCN is redundant, assuring that the
 cessing occurs. 1°3-m5It computationally processes, in a     network is fault or error tolerant, i.e, one or several
 multiprocessor network mode, the intercellular signals       inoperative cells causes little or no noticeable loss in
 created by an electrical type of mechanotransduction         network operations, 112 a matter of useful clinical
 of periosteal functional matrix stimuli. Subsequently        significance.
 the computed network output informational signals                The CCNs show oscillation, i.e., iterative recip-
 move hierarchically "upward" to regulate the skeletal       rocal signaling (feedback) between layers. This at-
 unit adaptational responses of the osteoblasts.             tribute enables them to adjustively self-organize.
      Fortunately, the bases of connectionist theory         This behavior is related to the fact that biologic
 are Sufficiently secure to permit modeling of a              CCNs are not preprogrammed; rather they learn by
biologically realistic osseous C C N . 1°6-11° It consists   unsupervised or epigenetic "training, ''114 a process
 of a number of relatively simple, densely intercon-         probably involving structural or conformational
nected processing elements (bone cells), with many           changes in the cytoskeleton. 83 The phenomena of
more interconnections than cells. It is useful that          both network "training" and "learning" are related
bone cells form a network because individual recep-          to the suggested effects of the oscillatory nature of
tors cannot code unambiguously-only a population             their strain history. 115 Accordingly, the structurally
of cells can do SO. 103                                      more complex network attributes and behavior of a
     In network theory, these cells are organized into       CCN gradually or epigenetically self-organize and
"layers": an initial input, a final output, and one or       emerge during operation. These network attributes
more intermediate or "hidden" layers. Importantly,           are not reducible, i.e., they are neither apparent nor
such networks need not be numerically complex to             predictable from a prior knowledge of the attributes
be operationally complex. H~ The operational pro-            of individual cells.
cesses are identical, in principle, for all bone cells in        Gap junctions, permitting bidirectional flow of
all layers. Regardless of the actual physiological           information, are the cytological basis for the oscil-
stipulatory process, each cell in any layer may simul-       latory behavior of a CCN. All the osteoblasts of a
taneously receive several "weighted" inputs (stimu-          cohort engaged in an identical adaptation process
li). A weight is some quantitative attribute. In the         are interconnected by open gap junctions. The pres-
initial layer, these represent the loadings. Within          ence of sharp histological discontinuities between
each cell independently, " . . . all the weighted inputs     cohorts of phenotypically different osteoblasts is
are then summed. ''112 This sum is then compared,            related to their ability to close gap junctions at the
within the cell, against some liminal or threshold           boundaries between such cohorts, and so prevent
value. If this value is exceeded, an intracellular           the flow of information. 116,1~7 Informational net-
signal is generated, i.e., successful mechanotrans-          works also can transmit inhibitory signals, a signifi-
duction occurs. This signal is then transmitted iden-        cant matter beyond present concerns. 118
tically to all the "hidden" layer cells (adjacent osteo-         A skeletal CCN displays the following attributes:
cytes) to which each initial layer cell is connected by      (1) Developmentally, it is an untrained self-orga-
gap junctions (and there are many styles of connec-          nized, self-adapting and epigenetically regulated sys-
tivity). Next, similar processes of weighted signal          tem. (2) Operationally, it is a stable, dynamic system
summation, comparison, and transmission occur in             that exhibits oscillatory behavior permitting feed-
these intermediate layers until the final layer cells        back. It operates in a noisy, nonstationary environ-
(osteoblasts) are reached. The outputs of these              ment, and probably uses useful and necessary inhib-
anatomically superficial cells determines the site,          itory inputs. (3) Structurally, an osseous CCN is
rate, direction, magnitude, and duration of the              nonmodular, i.e., the variations in its organization
specific adaptive response, i.e., deposition, resorp-        permit discrete processing of differential signals. It is
tion, and/or maintenance, of each cohort of osteo-           this attribute that permits the triad of histologic
blasts. ~13                                                  responses to a unitary loading event.
     Information is not stored discretely in a CCN, as           Certain simplifications exist in this article, as in
it is in a conventional, single CPU computer. Rather         most of the bone literature. It is assumed that bone
it is distributed across all or part of the network, and     cells are organized in only two dimensions, bone
several types of information may be stored simulta-          loadings occur only at discrete loci, and gradients of
neously. The instantaneous state of a CCN is a               strain are not considered. However, biologic reality
property of the state of all its cells and of all their      is otherwise. In a loaded three-dimensional bone
connections. Accordingly, the informational repre-           volume, gradients of deformation must exist, and
American Journal of Orthodontics and Dentofacial Orthopedics                                                  I~[OSS ~
Volume t12, No. 2


each osteocyte probably senses uniquely different                     Skeletal muscle contraction is a typical perios-
strain properties. Further, it is probable that each           teal functional matrix loading event, 13,14A6,12°,134'135
osteocyte is potentially able to transmit three differ-        and frequency is one of its critical parameters.
ent adaptational signals, in three different direc-            Although the fundamental frequency of contracting
tions-some stimulatory and some inhibitory. How-               muscle is about 2 Hz, other strain-related harmonics
ever, these processes have not yet been adequately             of 15 to 40 Hz exist.
modeled. The role of pe1~osteal functional matrices:                  These higher-order frequencies, significantly
new insight.                                                   related to bone adaptational responses, are
    The morphogenetic primacy of periosteal func-              " . . . present within the [muscle contraction] strain
tional matrices on their skeletal units is consensually        energy spectra regardless of animal or activity and
accepted. As a muscular demand alters, e.g., myec-             implicate the dynamics of muscle contraction as the
tomy, myotomy, neurectomy, exercise, hypertrophy,              source of this energy band" (italics mine). 68,132'~36 Of
hyperplasia, atrophy, augmentation, or reposition-             particular significance to the FMH is the close
ing, the triad of active bone growth processes cor-            similarity of muscle stimulus frequencies to bone
respondingly adapts the form of its specifically re-           tissue response frequencies.
lated skeletal unit.
    Presently excluding the stimulation of neural              MECHANOTRANSDUCTION: A TENTATIVE
afferents in muscle, tendon, and periosteum, extrin-           SYNTHESIS
sic physical loadings tend to deform bone tissue and                The previously mentioned data suggest that the
to invoke skeletal unit (bone) adaptation responsive           ability of periosteal functional matrices to regulate
processes. A classic example is the regulation of              the adaptive responses of their skeletal units by ionic
coronoid process form by the temporalis muscle.~9              mechanotransductive processes is related to several
The tension in the tendon of this contracted muscle,           factors. These are that (a) normal muscle function
transmitted through intertwined periosteal fibers              strains attached bone tissue intermittently; (b) the
inserted into subjacent bone, deforms the loaded               dynamics of skeletal muscle contraction fit rather
skeletal unit. 12°                                             nicely with the energetic requirements for bone cell
    Although some periosteal osteoNasts may be                 responsiveness; (c) the range of specific strain-
directly stimulated, ~2~ extant data suggest osteocytic        frequency harmonics of muscle dynamics are also
primacy in mechanosensory processes. ~22 Anatomi-              those found to be morphogenetically competent
cally, bone cells are competent mechanoreceptors.              (i.e., osteoregulatory); (d) normal skeletal muscle
Their three-dimensional array of extensive canalic-            activity produces intraosseous electric fields on the
ular cell processes is architecturally well-suited to          order of extrinsic fields found to be similarly mor-
sense deformation of the mineralized matrixJ 23                phogenetic; and, (e) bone cells may be stimulated by
    Although no one mechanical parameter reliably              two mechanisms-directly by strain-activated plasma
predicts all bone adaptational or remodeling re-               membrane channels and indirectly by electrokinen-
sponses, 124strain probably plays the primary role 125-128     tic phenomena.
and is a competent stimulus. 51 The significant strain              These factors strongly suggest a rather precise
attribute may vary with specific conditions. 129 These         matching of significant operational characteristics
include: (a) loading category-bone responds best to            between a contracting skeletal muscle stimulus and
dynamic rather static loading54; (b) frequency-osteo-          the ability of loaded bone cells to transduce this into
cytes may be physiologically "tuned" to the frequencies        signals capable of regulating their adaptive re-
of muscle function, 13°132 tunings being analogous to          sponses. In a phrase, bone appears to be closely
those of specialized nonosseous sensory cells,34,35 e.g.,      "tuned" to skeletal muscle, i.e., skeletal units are
auditory hair cells; and (c) magnitude-relatively small        tuned to their periosteal functional matrices.
microstrains (txe) (about 10-6 mm/mm), and strain                   When both the ionic membrane and the me-
magnitudes of 2000 + 1000 ge, are morphogenetically            chanical (molecular lever) transductive processes
competent.55,56,129.~33                                        are conceptually and operationally combined with
    Although it is reasonably presumed that mech-              the data of both electric field effects and of contrac-
anosensory processes, of both the ionic and mechan-            tion frequency energetics, they provide a logically
ical type, involve the plasma membrane of the                  sufficient biophysical basis of support for the hy-
osteocytic soma or canalicular processes, the recep-           pothesis of epigenetic regulation of skeletal tissue
tive, and subsequent transductive, processes are               adaptation 1,13,16-1s,38,129,137
neither well understood nor consensually agreed on.                 In reality, it is probable that the ionic (electrical)
224 Moss                                                                                              American Journal of Orthodontics and Dentofacial Orthopedics
                                                                                                                                                      August 1997


and mechanical (molecular lever) transductive pro-                                       16. Moss ML, Salentijn L. The primary role of the functional matrices in facial
                                                                                               growth. Arn J Orthod 1969;55:566-77.
cesses in osteocytes are neither exhaustive nor mu-                                       17. Moss ML, Salentijn L. The capsular matrix. Am J Orthod 1969;56:474-90.
tually exclusive. While using differing intermediate                                     18. Moss ML, Young R. A functional approach to craniology. Am J Phys Anthrop
                                                                                               1960;18:281-92.
membrane mechanisms or processes, they share a                                           19. Skalak R, Dasgupta G, Moss ML, Otten E, Dullemeijer P, Vilmann H. A
common final common pathway, i.e., they eventually                                            conceptual framework for the analytical description of growth. J Theor Biol
                                                                                               1982;94:555-77.
produce signals regulatory of osteoblastic activity.                                     20. Skalak R, Dasgupta G, Moss ML, Patel H, Sen K, Moss-Salentijn L. The
Certainly in the ionic processes, and possibly in the                                         application of the finite element method to the analysis of craniofacial growth and
                                                                                              form. Am J Orthod 1985;87:453-72.
molecular lever system mechanism, the transductive                                       21. Moss ML, Moss-Salentijn L, Skalak R. Finite element modeling of craniofacial
process(es) also cause a transplasma membrane                                                 growth and development. In: Graber L, editor. Orthodontics: stepping stones to
                                                                                              the future. St Louis: CV Mosby 1986:143-68.
ionic flow(s), creating a signal(s) capable of inter-                                    22. McAlarney M, Dasgupta G, Moss ML, Moss-Salentijn L. Anatomical macroele-
cellular transmission to neighboring bone cells                                               ments in the study of craniofacial rat growth. J Craniofac Genet Dev Biol
                                                                                               1992;12:3-12.
through gap junctions, 1~1 and then subsequent bio-                                      23. Pattee HH. Hiera~'chy theory: the challenge of complex systems. New York:
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                                                                                         24. Goldsmith P. Plant stems: a possible model system for the transduction of
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                                                                                         25. French AS. Mechanotransduction. Ann Rev Physiol 1992;54:135-52.
CONCLUSION                                                                               26. Kernan M, Cowan D, Zuker C. Genetic dissection of mechanoreception-defective
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                                                                                         27. Hamill OP, McBride DW Jr. Mechanoreceptive membrane channels. Am Scien-
descriptions of periosteal matrix function and skeletal unit                                  tist 1995;83:30-7.
response, the addition to the FMH of the concepts of                                     28. Hackney CM, Furness DN. Mechanotransduetion in vertebrate hair cells: struc-
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mechanotransduction and of computational bone biology                                    29. Fraser D J, Macdonald AG. Crab hydrostatic pressure sensors. Nature 1994;371:
offers an explanatory chain extending from the epigenetic                                     383-4.
event of skeletal muscle contraction, hierarchically down-                               30. Olsson S, Hanson BS. Action potentiablike activity found in fungal rnycelia is
                                                                                              sensitive to stimulation. Naturwissch 1995;82:30-1.
ward, through the cellular and molecular levels to the                                   31. Cut C, Smith DO, Adler J. Characterization of mechanosensitive channels in
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                                                                                         32. Wildron De, Thain JF, Minchin P, Gubb I, Reilly A, Skipper Y, et al. Electrical
changes. Analyzing size and shape changes by reference-                                       signaling and systematic proteinase inhibitor induction in the wounded planL
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American Journal of Orthodontics and Dent@cial Orthopedics                                                                                                             MOSS       ~
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The functional matrix hypothesis revisited.
3. The genomic thesis
           Melvin L. Moss, DDS, PhD
           New York, N. Y.

           Although the initial versions of the functional matrix hypothesis (FMH) theoretically posited the
           ontogenetic primacy of "function," it is only in recent years that advances in the morphogenetic,
           engineering, and computer sciences provided an integrated experimental and numerical data base
           that permitted recent significant revisions of the FMH--revisions that strongly support the primary
           role of function in craniofacial growth and development. Acknowledging that the currently dominant
           scientific paradigm suggests that genomic, instead of epigenetic (functional) factors, regulate
           (cause, control) such growth, an analysis of this continuing controversy was deemed useful.
           Accordingly the method of dialectical analysis, is employed, stating a thesis, an antithesis, and a
           resolving synthesis based primarily on an extensive review of the pertinent current literature. This
           article extensively reviews the genomic hypothesis and offers a critique intended to remove some of
           the unintentional conceptual obscurantism that has recently come to surround it. (Am J Orthod
           Dentofac Orthop 1997;112:338-42.)



"The whole plan of growth, the whole series of opera-                        Nevertheless, a continuing countercurrent of
tions to be carried out, the order and site of synthesis                 dissent claims morphogenesis is regulated (con-
and their co-ordination are all written down in the                      trolled, directed) by epigenetic mechanisms and
nucleic acid message. ''1                                                processes. 17-31 In addition, several new disciplines
                                                                         explicitly invoke epigenesis. 32-4z
"Within the fertilized egg lies the information necessary                    The epigenetic/genomic problem is a dichotomy,
to generate a diversity of cell types in the precise                     and dialectics is one analytical method for its reso-
pattern of tissues and organs that comprises the verte-                  lution. The method consists of the presentation of
brate body. ''2                                                          two opposing views, a thesis and an antithesis, and
                                                                         of a resolving synthesis. Such a dialectic analysis is
                                                                         presented here in two interrelated articles that
          T h e initial version of the functional matrix                 respectively consider (1) the genomic thesis and (2)
hypothesis (FMH), 3-8 claiming epigenetic control of                     an epigenetic antithesis and a resolving synthesis.
morphogenesis, was based on macroscopic (gross)                          Because a comprehensive review of this problem
experimental, comparative, and clinical data. Re-                        would be encyclopedic, only selected relevant as-
cently revised, 9,m it now extends hierarchically from                   pects of ontogeny (morphogenesis) and phylogeny
gross to microscopic (cellular and molecular) levels                     (evolution) are considered here.
and identifies some epigenetic mechanisms capable
of regulating genomic expression. This warranted
revisiting our earlier analysis of the perennial                         An Odontogenic Example of the
genomic/epigenetic controversy, n                                        Genomic/Epigenetic Dichotomy
    The epigenetic position of the F M H may seem                             Odontogenesis provides a comprehensible ex-
quixotic when molecular genetics is the premier                          ample. The widespread diagnostic use of vertebrate
ontogenetic research paradigm. Indeed, most clini-                       dental coronal morphology in zoological systemat-
cians and experimentalistsn-14--there are excep-                         ics, vertebrate paleontology, physical anthropology,
tions J~5 subscribe to the two epigraphs above, stated
                                                                         and forensic odontology suggests to many a rigid
more succinctly as "genes make us, body and mind. ''16
                                                                         genomic control of odontogenesis, as reflected in
From the Department of Anatomy and Cell Biology, College of Physicians   the temporally sequential, and spatially restricted,
and Surgeons, and School of Dental and Oral Surgery, Columbia Univer-
sity.
                                                                         expression of the genomically regulated production
Reprint requests to: Prof. Emeritus Melvin L. Moss, Department of        of specific molecules as exhibited, for example, in
Anatomyand CellBiology,ColumbiaUniversity,630 W. 168th.St., New          murine molar development. 43
York, NY 10032.e-mail:moss@civil.eolumbia.edu
Copyright© 1997by the AmericanAssociationof Orthodontists.                    Nevertheless, data exist strongly supportive of
0889-5406/97/$5.00 + 0   8/1/79952                                       epigenetic regulation of odontogenesis. For exam-
338
American Journal of Orthodontics and Dentofacial Orthopedics                                                 Moss 339
Volume 112, No. 3


ple, Chiclid fish are polyphyodont (have continu-              with the empirical data of animal breeders, it earlier
ously replacing dental sets) and can exhibit pro-              provided a theoretical basis for certain human eu-
nounced dental phenotypic plasticity.44 When the               genic theories proposing reproductive inhibition for
fish are fed on hard-shelled mollusks, the replacing           individuals with "undesirable and genetically (chro-
teeth are large and molariform, but when soft                  mosomally) regulated" medical and social condi-
food is fed, those teeth are gracile, conical, and             tions: a policy that eventually reached historical
nonmolariform. Experimentally in aquaria, the two              genocidal depths. 56,57
phenotypic states may be repeatedly and arbitrarily                Later, the blending of the classical chromosomal
alternated in succeeding dental generations by alter-          and vertebrate paleontological disciplines created
nately changing the diet's consistency. Because each           the neo-Darwinian synthesis, a currently accepted
dental replacement cycle involves identical odonto-            paradigm of phylogenetic regulation. 58
genic stages, it is postulated that (1) mechanical                 Recently, molecular (gene) genetics extended
forces, related to differential diet "hardness," gen-          the claims of the thesis to the regulation of all aspects
erate epigenetic signals, mechanotransductively pro-           of ontogeny (i.e., of "growth and development").
cessed by dental papilla cellsg.l°; and (2) these              The mega-human genome project, 59,6°~61called "the
signals control at least the temporal and spatial              ultimate triumph of genetics, ''4s explicitly intends to:
expression of genomic products related to the de-              (1) describe the complete human genome; (2) dem-
velopment of differential tooth form, such as size             onstrate genomic controls of all developmental pro-
and shape. 45-47                                               cesses, at all structural levels, from the subcellular to
    If the epigenetic/genomic dichotomy of odonto-             the organismal; and, (3) in a societal context, possi-
genetic regulation is unresolved, how much more so             bly lead to some type of neoeugenics.
the complex topic of cephalic morphogenesis where,                 Many human activities now are claimed to be
parenthetically, mechanical loadings also play a               genomically regulated: e.g., psychological behav-
significant regulatory role. 15                                ior6Z; personality63; alcohol and drug abuse64; chro-
                                                               nobiological cyclic behaviors65; smoking, obesity,
The Genomic Thesis                                             alcoholism, drug abuse, food-binging--indeed any
    The genomic thesis holds that the genome, from             attention-deficiency disorder, 66 among many others.
the moment of fertilization, contains all the infor-           The further suggestion of genomic control of intel-
mation necessary to regulate (cause, control, direct)          ligence generates prodigious, biomedical contro-
(1) the intranuclear formation and transcription of            versy in the social sciences and politics. 67 And note
mRNA and (2) importantly, without the later addi-              the frequent popular press reports of the "discov-
tion of any other information, to regulate also all of         ery" of yet another "gene" that "controls" yet an-
the intracellular and intercellular processes of sub-          other developmental, physiological, psychological,
sequent, and structurally more complex, cell, tissue,          or sociological event, process, or state.
organ, and organismal morphogenesisa'2,48: suc-
                                                               The Biologic Bases for the Genomic Thesis
cinctly, "all (phenotype) features are ultimately de-
termined by the DNA sequence of the genome. ''49                    While    comprehensively considered else-
    In this thesis, morphogenesis is but the prede-                             brief review is useful. The somatic
                                                               w h e r e , 48,49,53 a
termined reading-out of an intrinsic and inherited             cells of an individual metazoan inherit two classes of
genomic organismal blueprint 48'49'5°'51'52 where, in          molecular information: (1) an identical diploid
addition to molecular synthesis, the genome also               DNA and (2) the maternal cytoplasmic constituents
regulates the geometric attributes of cell, tissue,            of the egg: e.g., mitochondria, cytoskeleton, mem-
organ, and organismal size, shape, and location. For           branes. Only approximately 10% of the genome
example, "specific patterns of gene regulation                 seems related to phenotypic ontogenesis, whereas
(cause, control, regulate, determine) the mecha-               the human genome has approximately 100,000
nisms by which a fertilized egg divides and                    genes, "well over 90% ... does not encode precur-
progresses through the various decision points to              sors to mRNAs or any other RNA. ''53 With regard
yield groups of cells that are first determined to             to individual phenotypic structural attributes, while
become and then actually differentiate to become               all somatic cells commonly share approximately
specialized tissues of the right dimension and in the          5000 different polypeptide chains, each specific cell
proper location. ''s3                                          type is characterized only by approximately 100
    The genomic thesis originated with classical               specific proteins. And it is claimed that "these
(chromosomal) Mendelian genetics, s4,55 Combined               quantitative (protein) differences are related to dif-
340 Moss                                                            American Journal of Orthodontics and Dentofacial Orthopedics
                                                                                                                September 1997


ferences in cell size, shape and internal architec-         craniofacial development is controlled by two inter-
ture. ''s3                                                  related, temporally sequential, processes: (1) initial
     The encoding 10% of the DNA exists in two              regulatory (homeobox) gene activity and (2) subse-
families; the vastly preponderant "housekeeping"            quent activity of two regulatory molecular groups:
genes and the nonabundant "structural" genes. The           growth factor families and steroid/thyroid/retinoic
former regulate the normal molecular synthesis of           acid super-family. For example, "homeobox genes
agents involved in (1) the common energetic (met-           coordinate the development of complex craniofacial
abolic, respiratory) activities of all cells and, (2) the   structures" and in "both normal and abnormal de-
specific activities of special cell types (e.g., neurons,   velopment, much of the regulation of the develop-
osteoblasts, ameloblasts etc.). 52,68                       ment of virtually all of the skeletal and connective
     These genes also regulate the synthesis of the         tissue of the face is dependent on a cascade of
specific molecular gene products, whose presence,           overlapping activity of homeobox genes. ''12
absence, or abnormal molecular configuration are                It is claimed that regulatory molecules can (1)
associated with the (human) pathologic conditions           "alter the manner in which homeobox genes coor-
said to have a unitary genetic cause--the so-called         dinate cell migration and subsequent cell interac-
Mendelian disorders and the "single-gene disorders          tions that regulate growth" and (2) be involved in
with nonclassic inheritance, ''52 such as Marfan syn-       the "genetic variations causing, or contributing to,
drome, achondroplasia, osteogenesis imperfecta,             the abnormal development of relatively common
and Duchenne muscular dystrophy, among many                 craniofacial malformations . . . perhaps modifying
others. 52 For some, such "disorders provide the            Hox gene activity. ''52
model on which the program of medical genetics is               Specific orthodontic implications of the genomic
built. ''59 In such conditions the absence of a normal      thesis include claims that "poorly coordination-
type, or the presence of a structurally abnormal            ordinated control of form and size of structures, or
type, of a specific biochemical or molecular struc-         groups of structures (e.g., teeth and jaws) by regu-
tural entity is sufficient to initiate the cascade of       lator genes should do much to explain the very
subsequent abnormal developmental pathways,                 frequent mismatches found in malocclusions and
eventuating in a specific pathological state.               other dentofacial deformities." And "single regula-
    A physical analogy is the construction of a             tory (homeobox) genes can control the development
building wall where either the proportions of the           of complex structures.., indicating that single genes
concrete are incorrect or an insufficient number of         can determine the morphology of at least some
metal reinforcing rods are used. In both cases,             complex structures," including "how characteristic
eventual structural collapse is possible. Substitution      noses or jaws are inherited from generation to
of intercellular proteoglycans, and of collagen             generation. ''s2
fibrils, provides a corresponding skeletal tissue anal-
ogy. Here, alterations in the genomically regulated         Critical Definitions
processes of molecular synthesis can produce an                 Clarification of this dichotomy is assisted by
eventual "structural collapse" at the hierarchically        defining the present use of four terms: epigenetics,
higher level of a macroscopic bone. Anticipating an         hierarchy, emergence, and causation.
antithesis, note here that the claim of genomic                 Epigenetics. Several millennia ago epigenesis de-
control of the molecular syntheses underlying the           scribed the process(es) by which increasing struc-
formation of such elemental (molecular) skeletal            tural complexity gradually arose from an originally
tissue "building blocks" does not substantiate the          unstructured mass, for example the stages of in vivo
further claim that the genome regulates the growth          chick development or the gradual appearance of a
and development (the size, shape, location and histo-       pattern during weaving on a loom. 7s-81 Over time,
logical composition) of the gross anatomical bone.          many alternate, often differing, definitions ap-
                                                            peared. 22,82 Earlier, they were macroscopic in scale
The Genomic Thesis in Orofacial Biology                     and considered only the extrinsic, extraorganismal
    There is extensive support for the genomic thesis       environment, such as food, light, temperature, and
in the orofacial biology literature, with most genetic      radiations. 83 Nineteenth century physiology added
studies of cephalic or cranial morphogenesis explic-        the intrinsic, intraorganismal milieu interieur, s4 such
itly or implicitly assuming genomic regulation of           as hormones, blood gases, nutrients, and ions.
each anatomical structure. 69-77                                Epigenetics, as defined here, includes (1) all of
    A characteristic article 12 claims that prenatal        the extrinsic (extraorganismal) factors impinging on
American Journal of Orthodontics and Dentofacial Orthopedics                                                  Moss   341
Volume 112, No. 3


vital structures, including importantly mechanical             mandibular angular process of a given 14-year-old
loadings and electroelectric states and (2) all of the         male? The genomic thesis holds that this process
intrinsic (intraorganismal) biophysical, biomechani-           was predetermined; i.e, that individual's osteoblastic
cal, biochemical, and bioelectric microenvironmen-             genome contained, at the moment of fertilization,
tal events occurring on, in, and between individual            all the information necessary to regulate where,
cells, extracellular materials, and cells and extracel-        when, for how long, in what direction, in what
lular substances.                                              amount, and at what rates, bone formation and
    Hierarchy. Biological structures are hierarchically        remodeling will occur in that individual, given the
organized, with structural and functional complexity           absence of disease and the presence of the usual and
increasing "upward" from the ever-expanding family             necessary extrinsic (environmental) factors, such as
of subatomic particles to protons, electrons, atoms,           adequate nutrition, and the customary normal phys-
molecules, subcellular organelles, and on to cells,            iological states, such as are presumed to exist in
tissues, organs, and organisms. 4s While a genomic             physiology's hypothetical normal human.
thesis claims that each higher level is achieved by the             The antithesis (and the FMH) suggests that
predetermined activity of the genomic information,             epigenetic stimuli, created by operations of related
an epigenetic antithesis suggests that hierarchical            functional matrices and their skeletal unit adaptive
complexity results from the functioning of epi-                responses, create the "new" information sequen-
genetic processes and mechanisms, 3° as described              tially, as mandibular ontogenesis proceeds. 9,1° All
in the disciplines of developmental mechanicsy ,86             ontogenesis exhibits developmental "cascades," with
self-organization, 87 complexity, and chaos, 88,89,9°,91       multiple branching points where decisions are made
among others,--topics considered further in the                between alternate developmental pathways. Such
following epigenetic antithesis.                               decisions are not predetermined by encoded genetic
    Emergence. This phenomenon occurs in all nat-              information, but instead are responses to some
ural hierarchies. It consists of the appearance, at            epigenetic stimulus(i). Hierarchy, emergence, and
each successively higher and structurally and/or               causation are topics of the greatest significance in
operationally more complex level, of new attributes            any critique of the genomic hypothesis, because the
or properties, not present in the lower levels, whose          scope and content of molecular genetics is precisely
existence or functions could not in any way be                 that; it deals with only the molecular level of struc-
predicted, even from a complete knowledge of all of            tural organization. The genomic hypothesis pro-
the attributes and properties of any or all of the             poses no pathways from molecules to morphogene-
preceding lower organizational levels. 92-94                   sis? ° Customarily, in craniofacial literature, the
    For example, full knowledge of all the attributes          existence of two "facts" is stated: (1) that at the
and properties of an osteocyte does not permit                 molecular level, a particular gene (or group of
prediction of the attributes and properties of any             genes) exists and (2) that at some higher, macro-
type of bone tissue. And full knowledge of all                 scopic level, some clinical state of normal growth
attributes and properties of all constituent bone              and development or of malformation and/or mal-
tissue types does not permit prediction of the form            function is observed. Without positing any specific
(size and shape), growth, or functions of a macro-             mechanisms or processes at each intervening hier-
scopic "bone."                                                 archical level of the developmental cascade, it is
    Emergence is not genomically controlled. In-               simply stated that fact 1 is the cause of fact 2. For
stead, the integrated activities of all the attributes in      example, "it is demonstrated that synpolydactyly, an
a given hierarchical level self-organize to produce            inherited human abnormality of the hands and feet,
the next higher level of complexity. In every real             is caused [italics mine] by expansions of a polyala-
sense, biologic structures "build" themselves; that is,        nine stretch in the amino-terminal region of
bones do not grow, they are grown. Epigenetic                  HOXD13. ''97
processes and mechanisms are regulatory (causal) of                 In the genomic thesis morphogenesis is reduced
hierarchical organization and of emergence and                 to molecular synthesis.
self-organization. 95
                                                               T h e Classification of C a u s a t i o n 1t
    Causation. From this vast topic, 96 we consider
only how the attributes of a given biologic structural             There are four principal causes of ontogenesis:
level "cause" (control, regulate, determine) the at-           material (with what?), formal (by what rules?),
tributes of the next higher level. For example, what           efficient (how?), and final (why?). These may be
causes osteogenesis on the ectofacial surface the left         categorized as either intrinsic (material and formal)
342   Moss                                                              American Journal of Orthodontics and Dentofacial Orthopedics
                                                                                                                    September 1997


and extrinsic (efficient); final cause (teleology) is not      disks, and papers. The formal cause is the software:
considered further. Of importance, both material               a specific word processing program, both its appar-
and formal causes are classified as prior causes, i.e.,        ent, user-friend form and, in reality, its ultimate
existing before the creation of some specific state or         expression in machine language code. No combina-
structure. Efficient cause is proximate; i.e., its oper-       tion of hardware and software could ever write an
ation immediately causes the creation of a new state           article. Extrinsic, epigenetic input is required, i.e.,
or attribute. Material and formal causes are intrinsic         the composition and input of the text itself. Both
because they reside within vital structure (either             intrinsic causes must be present before (prior to) the
intracellularly or intercellularly); efficient causes are      textual input, whereas the extrinsic, epigenetic typ-
extrinsic--they represent the entire spectrum of               ing is immediately (i.e., proximately) followed by
epigenetic processes, mechanisms, and events capa-             creation, on the hard disk, of the text itself.
ble of being imposed on vital structures.                          Both prior (intrinsic) and proximate (extrinsic)
    In biology, material cause is represented by all           causes are necessary causes; neither alone is a
the levels of cellular and intercellular materials,            sufficient cause for the creation of this manuscript.
without reference to any specific structural (anatom-          Only the two integrated together furnish the neces-
ical) arrangement. Formal cause is the genomic                 sary and sufficient cause.
code, i.e., a series of "rules" or "laws." These act at            In ontogenesis, genomic (intrinsic, prior) and
the at the molecular level to regulate the initial             epigenetic (extrinsic, proximate) factors are each a
creation of the constituents of material cause. Effi-          necessary cause, but neither alone is a sufficient
cient cause(s) are the epigenetic factors, as defined          cause. Only the interaction of both provides both
above, whose actions immediately regulate the next             the necessary and sufficient cause of morphogene-
developmental branching point.                                 sisJ 1 This conclusion foreshadows the resolving
    A metaphor is helpful. Consider the use of a               synthesis of this dichotomy, presented in the com-
computer to prepare this manuscript. The material              panion article, which also contains the comprehen-
cause is the hardware: the computers, printers,                sive bibliography.




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Functional matrix hypothesis revisited. ajodo1997
Functional matrix hypothesis revisited. ajodo1997
Functional matrix hypothesis revisited. ajodo1997
Functional matrix hypothesis revisited. ajodo1997
Functional matrix hypothesis revisited. ajodo1997
Functional matrix hypothesis revisited. ajodo1997
Functional matrix hypothesis revisited. ajodo1997
Functional matrix hypothesis revisited. ajodo1997

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Functional matrix hypothesis revisited. ajodo1997

  • 1. SPECIAL ARTICLE The functional matrix hypothesis revisited. 1. The role of mechanotransduction Melvin L. Moss, DDS, PhD New York, N.Y. The periodic incorporation of advances in the biomedical, bioengineering, and computer sciences allow the creation of increasingly more comprehensive revisions of the functional matrix hypothesis. Inclusion of two topics, (1) the mechanisms of cellular mechanotransduction, and (2) biologic network theory, permit this latest revision; presented here in two interrelated articles. In this first article, the several possible types of intracellular processes of mechanotransduction are described. These translate the informational content of a periosteal functional matrix stimulus into a skeletal unit (bone) cell signal. The correlation between the strengths of the endogenous electrical fields produced by muscle skeletal muscle activity, and those to which bone cells maximally respond are stressed. Further, a physical chain of macromolecular levers, connecting the extracellular matrix to the bone cell genome is described, suggesting another means of epigenetic regulation of the bone cell genome, including its phenotypic expression. (Am J Orthod Dentofac Orthop 1997;112:8-11 .) Introduction. This series of four articles is a functional matrix over the years. This is the one cohesive and constructive perspective of "where we that will be referred to for decades to come, and are now after all the dust has settled." But, there is the one graduate students now will discuss in their another important and I think key feature and that seminars. is a discussion of functional matrix-type studies (by One point I would have liked Dr. Moss to have different names, perhaps) in other biologic disciplines addressed in greater depth in the final pages is how that otherwise we probably would be quite unaware of the functional matrix is involved in its own growth This in itself is a most noteworthy contribution, and development on how it is controlled. That is, because most of us, in both the basic and clinical how much genome and how do the provocative orthodontic sciences, are really not aware of ad- ideas of complexity and self-organization play into vances in other relevant fields. We can learn! Then, this? at the end, there is a look at the future, and this goes Donald Enlow conceptually beyond anything we presume to under- stand today. In all, Dr. Moss's assessment of his own T h i s article is presented as a series of work as a revision is, I think, more of a scholarly interrelated articles, of which this is the first. The elaboration, based on a broad quiltword of biologic second article contains both a comprehensive sum- understanding, now gleaned from a variety of other mary of this latest revision of the F M H as well as the specialties. reference list for both articles. There surely is room in our distinguished jour- nal, which has a solid reputation for recognizing DEVELOPMENT OF THE FUNCTIONAL MATRIX balance, for an introspective dissection of a biologic HYPOTHESIS (FMH) concept that has profound clinical meaning. When A decade's study of the regulatory roles of that concept is evaluated in the light of parallel intrinsic (genomic) and extrinsic (epigenetic) factors biologic theory, uncovered from other diverse fields, it presents a perspective for orthodontic scholars in cephalic growth evolved into the functional ma- available nowhere else. trix hypothesis (FMH). 1 This initial version, as aug- There are countless Moss references on the mented, 2 and stressing epigenetic primacy (as de- fined in Moss 3 and Herring4), became peer-accepted From the Department of Anatomy and Cell Biology, College of Physicians as one explanatory paradigm. and Surgeons, and School of Dental and Oral Surgery, Columbia Univer- sity. Periodically, incorporation of advances in the Reprint requests to: Prof. Emeritus Melvin L. Moss, Department of biomedical, bioengineering, and computer sciences Anatomy and Cell Biology, Columbia University, 630 W. 168th St., New have created more comprehensively explanatory York, NY 10032. e-mail: moss@cucersl.civil.columbia.edu Copyright © 1997 by the American Association of Orthodontists. F M H versions. 5,6 And recent work on two topics, 0889-5406/97/$5.00 + 0 8/1/70662 cellular transduction of informational signals and 8
  • 2. American Journal of Orthodontics and Dentofacial Orthopedics Moss 9 Volume 112, No. 1 biologic cellular network theory, permit the presen- cephalic growth, at the gross anatomic level, and it tation of this latest revision. 7-1° had two explanatory constraints: methodologic and hierarchical. THE CONCEPTUAL AND A N A T O M I C BASES OF 1. Methodologic constraint. Macroscopic mea- THE REVISED FMH surements, which use the techniques of point A comprehensible revision of the FMH should mechanics and arbitrary reference frames, e.g., indicate (a) those portions that are retained, ex- roentgenographic cephalometry, permitted only tended or discarded, and (b) which prior deficien- method-specific descriptions that cannot be struc- cies are now resolved. turally detailed. This constraint was removed by Although the principal FMH concepts are either the continuum mechanics techniques of the finite generally known or easily available, 1'11-18 three are element method (FEM) 6'1921 and of the related of particular resonance for this revision. macro and boundary element methods. 9,22 The developmental origin of all cranial skeletal This penultimate FEM revision added objective, elements (e.g., skeletal units) and all their subsequent reference-frame-invariant, fine-grained, and con- changes in size and shape (e.g., form) and location, as ceptually integrated descriptions of the quantitative well as their maintenance in being, are always, without aspects of localized cephalic growth kinematics to exception, secondary, compensatory, and mechanically the earlier qualitative (phenomenologic) descrip- obligatory responses to the temporally and operation- tions of growth dynamics. 4,6,9 ally prior demands of their related cephalic nonskel- 2. Hierarchical constraint. However, even that etal cells, tissues, organs, and operational volumes version's descriptions did not extend "downward" to (e.g., the functional matrices). processes at the cellular, subcellular, or molecular More precisely, the FMH claims that epigenetic, structural domains, or extend "upwards" to the extraskeletal factors and processes are the prior, multicellular processes by which bone tissues re- proximate, extrinsic, and primary cause of all adap- spond to lower level signals. All prior FMH versions tive, secondary responses of skeletal tissues and were "suspended" or "sandwiched" as it were, be- organs? It follows that the responses of the skeletal tween these two hierarchical levels. unit (bone and cartilage) cells and tissues are not Explicitly, the FMH could not describe either directly regulated by informational content of the how extrinsic, epigenetic FM stimuli are transduced intrinsic skeletal cell genome per se. Rather, this into regulatory signals by individual bone cells, or additional, extrinsic, epigenetic information is cre- how individual cells communicate to produce coor- ated by functional matrix operations. dinated multicellular responses. The F M H postulates two types of functional At the lower cellular or molecular levels, another matrices: periosteal and capsularJ 6'17 The former, problem exists. Almost uniformly, experimental and typified by skeletal muscles, regulates the histologi- theoretical studies of bone adaptation consider only cally observable active growth processes of skeletal the unicellular, unimolecular, or unigenomic levels. tissue adaptation. Accordingly, their results and derivative hypotheses This new version deals only with the responses to generally are not extensible to higher multicellular, periosteal matrices. It now includes the molecular and tissue, levels. cellular processes underlying the triad of active skele- Consequently, in prior FMH versions, significant tal growth processes: deposition, resorption, and main- disjunctions exist between the descriptions at each tenance. Histologic studies of actively adapting osse- of the several levels of bone organization. Such a ous tissues demonstrate that (1) adjacent adaptational hiatus is implicit in hierarchical theory in which the tissue surfaces simultaneously show deposition, re- attributes of successively higher levels are not simply sorption, and maintenance; (2) adaptation is a tissue the sum of lower level attributes. Rather, at each process. Deposition and maintenance are functions of higher level, new and more complex structural and relatively large groups (cohorts, compartments) of operational attributes arise that cannot be pre- homologous osteoblasts, never single cells; and (3) a dicted, even from a complete knowledge of those of sharp demarcation exists between adjacent cohorts of the lower levels23; e.g., the sum of all lower at- active, depository, and quiescent (resting) osteoblasts. tributes (biophysical, biochemical, genomic) of a bone cell cannot predict the higher attributes of a Constraints of the FMH bone tissue. Initially, the FMH ~,2 provided only qualitative At present, no unitary hypothesis provides a narrative descriptions of the biologic dynamics of comprehensive, coherent and integrated description
  • 3. 10 Moss American Journal of Orthodontics and Dentofacial Orthopedics July 1997 of all the processes and mechanisms involved in generally evoke one; (3) osseous signal transmission bone growth, remodeling, adaptation, and mainte- is aneural, whereas all other mechanosensational nance at all structural levels. This newest FMH signals use some afferent neural pathways28.41; and, version, presented herein, transcends some hierar- (4) the evoked bone adaptational responses are chical constraints and permits seamless descriptions confined within each "bone organ" independently, at, and between, the several levels of bone structure e.g., within a femur, so there is no necessary "inter- and operation-from the genomic to the organ level. bone" or organismal involvement. It does so by the inclusion of two complementary This process translates the information content concepts: (1) that mechanotransduction occurs in of a periosteal functional matrix stimulus into a single bone cells, and (2) that bone cells are com- skeletal unit cell signal, for example, it moves infor- putational elements that function multicellularly as mation hierarchically downward to the osteocytes. a connected cellular network. There are two, possibly complementary, skeletal It is useful to present the database and derivative cellular mechanotransductive processes: ionic and theories, supportive of the inclusion of these two mechanical. concepts individually in a series of two coordinated Ionic or electrical processes. This involves some articles: the first on mechanotransduction and the process(es) of ionic transport through the bone cell second on connected cellular networks. (osteocytic) plasma membrane. There is a subse- quent intercellular transmission of the created ionic Mechanotransduction or electrical signals that, in turn, are computed by All vital ceils are "irritable" or perturbed by and the operation of an osseous connected cellular respond to alterations in their external environment. network (CCN), as described in the second article in Mechanosensing processes enable a cell to sense this series. That network's output regulates the and to respond to extrinsic loadings, a widespread multicellular bone cell responses. 1°,42 biologic attribute, 24-32 by using the processes of Although no consensual agreement exists, osteo- mechanoreception and of mechanotransduction. cytic, ionic-mechanotransduction may involve sev- The former transmits an extracellular physical stim- eral, possibly parallel, cellular processes. ulus into a receptor cell; the latter transduces or Stretch-activated channels. Several types of defor- transforms the stimulus's energetic and/or informa- mation may occur in strained bone tissue. One of tional content into an intracellular signal. Mechano- these involves the plasma membrane stretch-acti- transduction33 is one type of cellular signal transduc- vated (S-A) ion channels, a structure found in bone tion. 34-36 There are several mechanotransductive cells, 43-46 in many other cell types,25 and significantly processes, for example, mechanoelectrical and in fibroblasts. 4v When activated in strained osteo- mechanochemical. Whichever are used, bone adap- cytes, they permit passage of a certain sized ion or tation requires the subsequent intercellular trans- set of ions, including K +, Ca 2+, Na +, and CS+. 46'48-50 mission of the transduced signals. Such ionic flow may, in turn, initiate intracellular electrical events, for example, bone cell S-A chan- Osseous Mechanotransduetion nels may modulate membrane potential as well as Static37 and dynamic3s loadings are continuously Ca 2+ ion fluxY ,5~ Other bone cell mechanically applied to bone tissues, tending to deform both stimulatory processes have been suggested.52 extracellular matrix and bone cells. When an appro- Rough estimates of osteocytic mechanoreceptor priate stimulus parameter exceeds threshold values, strain sensitivity have been made, 1°,53 and the calcu- the loaded tissue responds by the triad of bone cell lated values cover the morphogenetically significant adaptation processes. Both osteocytes and osteo- strain range of 1000 to 3000 txe in the literature. 54-56 blasts are competent for intracellular stimulus re- Electrical processes. These include several, non- ception and transduction and for subsequent inter- exclusive mechanotransductive processes (e.g., elec- cellular signal transmission. Osteoblasts directly tromechanical and electrokinetic), involving the regulate bone deposition and maintenance and in- plasma membrane and extracellular fluids. Electric directly regulate osteoclastic resorption. 39,4° field strength may also be a significant parameterF Osseous mechanotransduction is unique in four ways: (1) Most other mechanosensory cells are 1. Electromechanical. As in most cells, the osteo- cytologically specialized, but bone cells are not; (2) cytic plasma membrane contains voltage-acti- one bone-loading stimulus can evoke three adapta- vated ion channels, and transmembrane ion tional responses, whereas nonosseous processes flow may be a significant osseous mechano-
  • 4. American Journal of Orthodontics and Dentofacial Orthopedics Moss 11 Volume 112, No. 1 transductive p r o c e s s . 58'59'6°-62 It is also possi- alternative means by which periosteal functional ble that such ionic flows generate osteocytic matrix activity may regulate hierarchically lower action potentials capable of transmission level bone cell genomic functions. through gap junctions. 63 The mechanical properties of the extracellular 2. Electrokinetic. Bound and unbound electric matrix influence cell behavior. 71 Loaded mineral- charges exist in bone tissue, many associated ized bone matrix tissue is deformed or strained. with the bone fluid(s) in the several osseous Recent data indicate that a series of extracellular spaces or compartments. 42,64 It is generally macromolecular mechanical levers exist, capable of agreed that electrical effects in fluid-filled transmitting information from the strained matrix to bone are not piezoelectric, but rather of elec- the bone cell nuclear membrane. trokinetic, that is, streaming potential (SP) The basis of this mechanism is the physical origin. 42'65'66 The SP is a measure of the continuity of the transmembrane molecule integrin. strain-generated potential (SGP) of con- This molecule is connected extracellularly with the vected electric charges in the fluid flow of macromolecular collagen of the organic matrix and deformed bone. The usually observed SPG of intracellularly with the cytoskekeletal actin. The +2 mV can initiate both osteogenesis and molecules of the latter, in turn, are connected to the osteocytic action potentials. 66'67 nuclear membrane, at which site the action of the 3. Electric field strength. Bone responds to exog- mechanical lever chain previously noted initiates a enous electrical fields. 68 Although the extrin- subsequent series of intranuclear processes regula- sic electrical parameter is unclear, field tory of genomic activity. 72-75 (See Shapiro et al., 76 for strength may play an important role. 69 A vimentin, and Green 77 for a general discussion of significant parallel exists between the param- biophysical transductions.) eters of these exogenous electrical fields 68,69 It is suggested that such a cytoskeletal lever and the endogenous fields produced by mus- chain, connecting to the nuclear membrane, can cle activity. Bone responds to exogenous elec- provide a physical stimulus able to activate the trical fields in an effective range of 1 to 10 osteocytic genome, 78 possibly by first stimulating the ixV/cm, strengths that are "...on the order of activity of such components as the cfos those endogenously produced in bone tissue genes.36,73, 78-86 during normal (muscle) activity "7° (italics It is by such an interconnected physical chain of mine). molecular levers that periosteal functional matrix Mechanical processes. Although it is probable activity may regulate the genomic activity of its that the intracellular, transductive process discussed strained skeletal unit bone cells, including their later does not initiate action potentials, it is an phenotypic expression.
  • 5. The functional matrix hypothesis revisited. 2. The role of an osseous connected cellular network Melvin L. Moss, DDS, PhD New York, N.Y.. Intercellular gap junctions permiz bone cells to intercellularly transmit, and subsequently process, periosteal functional matrix information, after its initial intraceilular mechanotransduction. In addition, gap junctions, as electrical synapses, underlie the organization of bone tissue as a connected cellular network, and the fact that all bone adaptation processes are multicellular. The structural and operational characteristics of such biologic networks are outlined and their specific bone cell attributes described. Specifically, bone is "tuned" to the precise frequencies of skeletal muscle activity. The inclusion of the concepts and databases that are related to the intracellular and intercellular bone cell mechanisms and processes of mechanotransduction and the organization of bone as a biologic connected cellular network permit revision of the functional matrix hypothesis, which offers an explanatory chain, extending from the epigenetic event of muscle contraction hierarchically downward to the regulation of the bone cell genome. (Am J Orthod Dentofac Orthop 1997;112:221-6.) T h e first article in this series considered processes meet. 93 In compact bone, the canaliculi the implications for the functional matrix hypothesis cross "cement lines," and they form extensive com- (FMH) of the ability of bone cells to carry out munications between osteons and interstitial re- intracellular mechanosensation and transduction gions. 94 Gap junctions also connect superficial os- and intercellular communication. In this article, we teocytes to periosteal and endOsteal osteoblasts. All will consider the implications for the FMH of the osteoblasts are similarly interconnected laterally. inclusion of connectionist network theory. Vertically, gap junctions connect periosteal osteo- blasts with preosteoblastic cells, and these, in turn, BONE AS AN OSSEOUS CONNECTED CELLULAR are similarly interconnectedY Effectively, each NETWORK (CCN) CCN is a true syncytium. 87,91,93Bone cells are elec- All bone cells, except osteoclasts, are extensively trically active. 57,Ss,sS,95-ml In a very real sense, bone interconnected by gap junctions 8791 that form an tissue is "hard-wired. ''7,s,96 o s s e o u s C C N . 7,8,42 In these junctions, connexin 43 is In addition to permitting the intercellular trans- the major protein. 92 Each osteocyte, enclosed within mission of ions and small molecules, gap junctions its mineralized lacuna, has many (n = +80) cyto- exhibit both electrical and fluorescent dye transmis- plasmic (canalicular) processes, _+15 ~m long and sion. 63 Gap junctions are electrical synapses, in arrayed three-dimensionally, that interconnect with contradistinction to interneuronal, chemical syn- similar processes of up to 12 neighboring cells. apses, and, significantly, they permit bidirectional These processes lie within mineralized bone matrix signal traffic, e.g., biochemical, ionic. channels (canaliculi). The small space between the Mechanotransductively activated bone cells, e.g., cell process plasma membrane and the canaticular osteocytes, can initiate membrane action potentials wall is filled macromolecular complexes. capable of transmission through interconnecting gap Gap junctions are found where the plasma mem- junctions. The primacy of ionic signals rather than branes of a pair of markedly overlapping canalicular secondary messengers is suggested here, because, although bone cell transduction may also produce From the Department of Anatomy and Cell Biology, Co]lege of Physicians and Surgeons, and School of Dental and Oral Surgery, Columbia Univer- small biochemical molecules that can pass through sity. gap junctions, the time-course of mechanosensory Reprint requests to: Prof. Emeritus Melvin L. Moss, Department of processes is believed to be too rapid for the involve- Anatomy and Cell Biology, 630 W. 168th St., New York, NY 10032. e-mail: moss@cucersl.civil.columbia.edu ment of secondary messengersY. 32 (See Carvalho et Copyright © 1997 by the American Association of Orthodontists. al. 1°2 for an opposite view.) A CCN is operationally 0889-5406/97/$5.00 + 0 8/1/70663 analogous to an "artificial neural network," in which 221
  • 6. 222 Moss American Journal of Orthodontics and Dentofacial Orthopedics August 1997 massively parallel or parallel-distributed signal pro- sentation of CCN is redundant, assuring that the cessing occurs. 1°3-m5It computationally processes, in a network is fault or error tolerant, i.e, one or several multiprocessor network mode, the intercellular signals inoperative cells causes little or no noticeable loss in created by an electrical type of mechanotransduction network operations, 112 a matter of useful clinical of periosteal functional matrix stimuli. Subsequently significance. the computed network output informational signals The CCNs show oscillation, i.e., iterative recip- move hierarchically "upward" to regulate the skeletal rocal signaling (feedback) between layers. This at- unit adaptational responses of the osteoblasts. tribute enables them to adjustively self-organize. Fortunately, the bases of connectionist theory This behavior is related to the fact that biologic are Sufficiently secure to permit modeling of a CCNs are not preprogrammed; rather they learn by biologically realistic osseous C C N . 1°6-11° It consists unsupervised or epigenetic "training, ''114 a process of a number of relatively simple, densely intercon- probably involving structural or conformational nected processing elements (bone cells), with many changes in the cytoskeleton. 83 The phenomena of more interconnections than cells. It is useful that both network "training" and "learning" are related bone cells form a network because individual recep- to the suggested effects of the oscillatory nature of tors cannot code unambiguously-only a population their strain history. 115 Accordingly, the structurally of cells can do SO. 103 more complex network attributes and behavior of a In network theory, these cells are organized into CCN gradually or epigenetically self-organize and "layers": an initial input, a final output, and one or emerge during operation. These network attributes more intermediate or "hidden" layers. Importantly, are not reducible, i.e., they are neither apparent nor such networks need not be numerically complex to predictable from a prior knowledge of the attributes be operationally complex. H~ The operational pro- of individual cells. cesses are identical, in principle, for all bone cells in Gap junctions, permitting bidirectional flow of all layers. Regardless of the actual physiological information, are the cytological basis for the oscil- stipulatory process, each cell in any layer may simul- latory behavior of a CCN. All the osteoblasts of a taneously receive several "weighted" inputs (stimu- cohort engaged in an identical adaptation process li). A weight is some quantitative attribute. In the are interconnected by open gap junctions. The pres- initial layer, these represent the loadings. Within ence of sharp histological discontinuities between each cell independently, " . . . all the weighted inputs cohorts of phenotypically different osteoblasts is are then summed. ''112 This sum is then compared, related to their ability to close gap junctions at the within the cell, against some liminal or threshold boundaries between such cohorts, and so prevent value. If this value is exceeded, an intracellular the flow of information. 116,1~7 Informational net- signal is generated, i.e., successful mechanotrans- works also can transmit inhibitory signals, a signifi- duction occurs. This signal is then transmitted iden- cant matter beyond present concerns. 118 tically to all the "hidden" layer cells (adjacent osteo- A skeletal CCN displays the following attributes: cytes) to which each initial layer cell is connected by (1) Developmentally, it is an untrained self-orga- gap junctions (and there are many styles of connec- nized, self-adapting and epigenetically regulated sys- tivity). Next, similar processes of weighted signal tem. (2) Operationally, it is a stable, dynamic system summation, comparison, and transmission occur in that exhibits oscillatory behavior permitting feed- these intermediate layers until the final layer cells back. It operates in a noisy, nonstationary environ- (osteoblasts) are reached. The outputs of these ment, and probably uses useful and necessary inhib- anatomically superficial cells determines the site, itory inputs. (3) Structurally, an osseous CCN is rate, direction, magnitude, and duration of the nonmodular, i.e., the variations in its organization specific adaptive response, i.e., deposition, resorp- permit discrete processing of differential signals. It is tion, and/or maintenance, of each cohort of osteo- this attribute that permits the triad of histologic blasts. ~13 responses to a unitary loading event. Information is not stored discretely in a CCN, as Certain simplifications exist in this article, as in it is in a conventional, single CPU computer. Rather most of the bone literature. It is assumed that bone it is distributed across all or part of the network, and cells are organized in only two dimensions, bone several types of information may be stored simulta- loadings occur only at discrete loci, and gradients of neously. The instantaneous state of a CCN is a strain are not considered. However, biologic reality property of the state of all its cells and of all their is otherwise. In a loaded three-dimensional bone connections. Accordingly, the informational repre- volume, gradients of deformation must exist, and
  • 7. American Journal of Orthodontics and Dentofacial Orthopedics I~[OSS ~ Volume t12, No. 2 each osteocyte probably senses uniquely different Skeletal muscle contraction is a typical perios- strain properties. Further, it is probable that each teal functional matrix loading event, 13,14A6,12°,134'135 osteocyte is potentially able to transmit three differ- and frequency is one of its critical parameters. ent adaptational signals, in three different direc- Although the fundamental frequency of contracting tions-some stimulatory and some inhibitory. How- muscle is about 2 Hz, other strain-related harmonics ever, these processes have not yet been adequately of 15 to 40 Hz exist. modeled. The role of pe1~osteal functional matrices: These higher-order frequencies, significantly new insight. related to bone adaptational responses, are The morphogenetic primacy of periosteal func- " . . . present within the [muscle contraction] strain tional matrices on their skeletal units is consensually energy spectra regardless of animal or activity and accepted. As a muscular demand alters, e.g., myec- implicate the dynamics of muscle contraction as the tomy, myotomy, neurectomy, exercise, hypertrophy, source of this energy band" (italics mine). 68,132'~36 Of hyperplasia, atrophy, augmentation, or reposition- particular significance to the FMH is the close ing, the triad of active bone growth processes cor- similarity of muscle stimulus frequencies to bone respondingly adapts the form of its specifically re- tissue response frequencies. lated skeletal unit. Presently excluding the stimulation of neural MECHANOTRANSDUCTION: A TENTATIVE afferents in muscle, tendon, and periosteum, extrin- SYNTHESIS sic physical loadings tend to deform bone tissue and The previously mentioned data suggest that the to invoke skeletal unit (bone) adaptation responsive ability of periosteal functional matrices to regulate processes. A classic example is the regulation of the adaptive responses of their skeletal units by ionic coronoid process form by the temporalis muscle.~9 mechanotransductive processes is related to several The tension in the tendon of this contracted muscle, factors. These are that (a) normal muscle function transmitted through intertwined periosteal fibers strains attached bone tissue intermittently; (b) the inserted into subjacent bone, deforms the loaded dynamics of skeletal muscle contraction fit rather skeletal unit. 12° nicely with the energetic requirements for bone cell Although some periosteal osteoNasts may be responsiveness; (c) the range of specific strain- directly stimulated, ~2~ extant data suggest osteocytic frequency harmonics of muscle dynamics are also primacy in mechanosensory processes. ~22 Anatomi- those found to be morphogenetically competent cally, bone cells are competent mechanoreceptors. (i.e., osteoregulatory); (d) normal skeletal muscle Their three-dimensional array of extensive canalic- activity produces intraosseous electric fields on the ular cell processes is architecturally well-suited to order of extrinsic fields found to be similarly mor- sense deformation of the mineralized matrixJ 23 phogenetic; and, (e) bone cells may be stimulated by Although no one mechanical parameter reliably two mechanisms-directly by strain-activated plasma predicts all bone adaptational or remodeling re- membrane channels and indirectly by electrokinen- sponses, 124strain probably plays the primary role 125-128 tic phenomena. and is a competent stimulus. 51 The significant strain These factors strongly suggest a rather precise attribute may vary with specific conditions. 129 These matching of significant operational characteristics include: (a) loading category-bone responds best to between a contracting skeletal muscle stimulus and dynamic rather static loading54; (b) frequency-osteo- the ability of loaded bone cells to transduce this into cytes may be physiologically "tuned" to the frequencies signals capable of regulating their adaptive re- of muscle function, 13°132 tunings being analogous to sponses. In a phrase, bone appears to be closely those of specialized nonosseous sensory cells,34,35 e.g., "tuned" to skeletal muscle, i.e., skeletal units are auditory hair cells; and (c) magnitude-relatively small tuned to their periosteal functional matrices. microstrains (txe) (about 10-6 mm/mm), and strain When both the ionic membrane and the me- magnitudes of 2000 + 1000 ge, are morphogenetically chanical (molecular lever) transductive processes competent.55,56,129.~33 are conceptually and operationally combined with Although it is reasonably presumed that mech- the data of both electric field effects and of contrac- anosensory processes, of both the ionic and mechan- tion frequency energetics, they provide a logically ical type, involve the plasma membrane of the sufficient biophysical basis of support for the hy- osteocytic soma or canalicular processes, the recep- pothesis of epigenetic regulation of skeletal tissue tive, and subsequent transductive, processes are adaptation 1,13,16-1s,38,129,137 neither well understood nor consensually agreed on. In reality, it is probable that the ionic (electrical)
  • 8. 224 Moss American Journal of Orthodontics and Dentofacial Orthopedics August 1997 and mechanical (molecular lever) transductive pro- 16. Moss ML, Salentijn L. The primary role of the functional matrices in facial growth. Arn J Orthod 1969;55:566-77. cesses in osteocytes are neither exhaustive nor mu- 17. Moss ML, Salentijn L. The capsular matrix. Am J Orthod 1969;56:474-90. tually exclusive. While using differing intermediate 18. Moss ML, Young R. A functional approach to craniology. Am J Phys Anthrop 1960;18:281-92. membrane mechanisms or processes, they share a 19. Skalak R, Dasgupta G, Moss ML, Otten E, Dullemeijer P, Vilmann H. A common final common pathway, i.e., they eventually conceptual framework for the analytical description of growth. J Theor Biol 1982;94:555-77. produce signals regulatory of osteoblastic activity. 20. Skalak R, Dasgupta G, Moss ML, Patel H, Sen K, Moss-Salentijn L. The Certainly in the ionic processes, and possibly in the application of the finite element method to the analysis of craniofacial growth and form. Am J Orthod 1985;87:453-72. molecular lever system mechanism, the transductive 21. Moss ML, Moss-Salentijn L, Skalak R. Finite element modeling of craniofacial process(es) also cause a transplasma membrane growth and development. In: Graber L, editor. Orthodontics: stepping stones to the future. St Louis: CV Mosby 1986:143-68. ionic flow(s), creating a signal(s) capable of inter- 22. McAlarney M, Dasgupta G, Moss ML, Moss-Salentijn L. Anatomical macroele- cellular transmission to neighboring bone cells ments in the study of craniofacial rat growth. J Craniofac Genet Dev Biol 1992;12:3-12. through gap junctions, 1~1 and then subsequent bio- 23. Pattee HH. Hiera~'chy theory: the challenge of complex systems. New York: logic computation in an osseous CCN. G.Baziller, 1973. 24. Goldsmith P. Plant stems: a possible model system for the transduction of mechanical information in bone modeling. Bone 1994;15:249-50. 25. French AS. Mechanotransduction. Ann Rev Physiol 1992;54:135-52. CONCLUSION 26. Kernan M, Cowan D, Zuker C. Genetic dissection of mechanoreception-defective Where the original FMH version offered only verbal mutations in Drosophila. Neuron 1994;12:1195-206. 27. Hamill OP, McBride DW Jr. Mechanoreceptive membrane channels. Am Scien- descriptions of periosteal matrix function and skeletal unit tist 1995;83:30-7. response, the addition to the FMH of the concepts of 28. Hackney CM, Furness DN. Mechanotransduetion in vertebrate hair cells: struc- ture and function of the stereociliary bundle. Am J Physiol 1995;268:C1-13. mechanotransduction and of computational bone biology 29. Fraser D J, Macdonald AG. Crab hydrostatic pressure sensors. Nature 1994;371: offers an explanatory chain extending from the epigenetic 383-4. event of skeletal muscle contraction, hierarchically down- 30. Olsson S, Hanson BS. Action potentiablike activity found in fungal rnycelia is sensitive to stimulation. Naturwissch 1995;82:30-1. ward, through the cellular and molecular levels to the 31. Cut C, Smith DO, Adler J. Characterization of mechanosensitive channels in bone cell genome, and then upward again, through histo- Eschericia colt cytoplasmic cell membrane by whole-cell patch clamp recording. J logic levels to the event of gross bone form adaptational Membr Biol 1995;144:31-42. 32. Wildron De, Thain JF, Minchin P, Gubb I, Reilly A, Skipper Y, et al. Electrical changes. Analyzing size and shape changes by reference- signaling and systematic proteinase inhibitor induction in the wounded planL frame-invariant, finite element methods produces a more Nature 1992;360:62-5. 33. Mayer EA. Signal transduetion and intercellular communication. In: Walsh JH, comprehensive and integrated description of the totality Dockray G J, editors. Gut peptides: biochemistry and physiology. New York: of the processes of epigenetic regulation of bone form Raven Press, 1994:33-73. than previously possible. 34. Martin J. Coding and processing of sensory information. In: Kandel ER, Schwartz JH, Jessel TM, editors. Principles of neural science. 3rd. ed. New York: Elsevier, 1991:329-40. 35. Martin J, Jessel TM. Modality coding in the somatic sensory system. In: Kandel REFERENCES ER, Schwartz JH, Jessel TM, editors. 3rd. ed. New- York: Elsevier, 1991:341-52. 36. Wang N, Butler JP, Ingber DE. Mechanotransduction across the cell surface and 1. Moss ML. The functional matrix. In: Kraus B, Reidel R, editors. Vistas in through the cTtoskeleton. Science 1993;260:1124-7. orthodontics. Philadelphia: Lea and Febiger, 1962:85-98. 37. Claassen DE, Spooner BS. Impact of altered gravity on aspects of cell biolo~, lot 2. Moss ML. 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  • 10. 226 Moss American Journal of Orthodontics and Dentofacial Orthopedics August 1997 122. Aarden EM, Burger EH, Nijweide PJ. Function of osteocytes in bone. J Cell 131. Turner CH. Functional determinants of bone structure: beyond WollFs law of Biochem 1994;55:287-99. bone transformation. Editorial. Bone 1992;13:403-9. 123. Lanyon LE. Osteocytes, strain detection, bone modeling and remodeling. Calcif 132. Rubin CT, Donahue HJ, Rubin JE, McLeod KI. Optimization of electric field Tiss Int 1993;53:$102-6. parameters for the control of bone remodeling: exploitation of an indigenous 124. Brown TD, Pederseu DR, Gray ML, Brand RA, Rubin CT. Periosteal remodel- mechanism for the prevention of osteopenia. J Bone Miner Res 1993;8:$573-81. ing: a combined experimental and analytic approach. J Biomech 1990;23:893-905. 133. Turner CH, Forwood MR, Rho J-Y, Yoshikawa T. Mechanical loading thresholds 125. Cowin SC. Strain assessment by bone cells. In: Skalak R, Fox CF, editors. Tissue for lamellar and woven bone formation. J Bone Miner Res 1993;9:87-97. Engineering. New York: Alan R. Liss, 1988:181-7. 134. Moss ML. A theoretical analysis of the functional matrix. Acta Biotheor 1969;18: 126. Cowin SC. Bone biomechanics. Boca Raton: CRC Press, 1989a. 195-202. 127. Cowin SC. A resolution restriction for Wolff's law of trabecular architecture. Bull 135. Moss ML. Functional cranial analysis of the mandibular angular cartilage in the Hosp Jt Dis 1989;49:205-12. rat. Angle Orthod 1969;39:209-14. 128. Rubin LE, McLeod KJ, Bain SD. Functional strains and cortical bone adaptation: 136. Rodrequez AA, Agre JC, Knudston ER, NG A. Acoustic myography compared to epigenetic assurance of skeletal integrity. J Biomech 1990;25:43-54. electromyography during isometric fatigue and recovery. Muscle Nerve 1993;16: 129. Martin RB, Burr DB. Structure, function and adaptation of compact bone. New 188-92. York: Raven Press, 1989. 137. Moss ML. The functional matrix hypothesis and epigenetics. In: Graber TM, 130. McLeod KL, Rubin CT. The effect of low-frequency electrical fields on osteo- editor. Physiologic principles of functional appliances. St Louis: CV Mosby, genesis. J Bone Jt Surg I992;74A:920-9. 1985:3-4. AVAILABILITY OF JOURNAL BACK ISSUES As a service to our subscribers, copies of back issues of the American Journal of Orthodontics and Dentofacial Orthopedics for the preceding 5 years are maintained and are available for purchase from the publisher, Mosby-Year Book, Inc., at a cost of $11.00 per issue. The following quantity discounts are available: 25% off on quantities of 12 to 23, and one third off on quantities of 24 or more. Please write to Mosby-Year Book, Inc., Subscription Services, 11830 Westline Industrial Dr., St. Louis, MO 63146-3318, or call (800)453-4351 or (314)453-4351 for information on availability of particular issues. If unavailable from the publisher, photocopies of complete issues are available from University Microfilms International, 300 N. Zeeb Rd., Ann Arbor, MI 48106 (313)761-4700.
  • 11. The functional matrix hypothesis revisited. 3. The genomic thesis Melvin L. Moss, DDS, PhD New York, N. Y. Although the initial versions of the functional matrix hypothesis (FMH) theoretically posited the ontogenetic primacy of "function," it is only in recent years that advances in the morphogenetic, engineering, and computer sciences provided an integrated experimental and numerical data base that permitted recent significant revisions of the FMH--revisions that strongly support the primary role of function in craniofacial growth and development. Acknowledging that the currently dominant scientific paradigm suggests that genomic, instead of epigenetic (functional) factors, regulate (cause, control) such growth, an analysis of this continuing controversy was deemed useful. Accordingly the method of dialectical analysis, is employed, stating a thesis, an antithesis, and a resolving synthesis based primarily on an extensive review of the pertinent current literature. This article extensively reviews the genomic hypothesis and offers a critique intended to remove some of the unintentional conceptual obscurantism that has recently come to surround it. (Am J Orthod Dentofac Orthop 1997;112:338-42.) "The whole plan of growth, the whole series of opera- Nevertheless, a continuing countercurrent of tions to be carried out, the order and site of synthesis dissent claims morphogenesis is regulated (con- and their co-ordination are all written down in the trolled, directed) by epigenetic mechanisms and nucleic acid message. ''1 processes. 17-31 In addition, several new disciplines explicitly invoke epigenesis. 32-4z "Within the fertilized egg lies the information necessary The epigenetic/genomic problem is a dichotomy, to generate a diversity of cell types in the precise and dialectics is one analytical method for its reso- pattern of tissues and organs that comprises the verte- lution. The method consists of the presentation of brate body. ''2 two opposing views, a thesis and an antithesis, and of a resolving synthesis. Such a dialectic analysis is presented here in two interrelated articles that T h e initial version of the functional matrix respectively consider (1) the genomic thesis and (2) hypothesis (FMH), 3-8 claiming epigenetic control of an epigenetic antithesis and a resolving synthesis. morphogenesis, was based on macroscopic (gross) Because a comprehensive review of this problem experimental, comparative, and clinical data. Re- would be encyclopedic, only selected relevant as- cently revised, 9,m it now extends hierarchically from pects of ontogeny (morphogenesis) and phylogeny gross to microscopic (cellular and molecular) levels (evolution) are considered here. and identifies some epigenetic mechanisms capable of regulating genomic expression. This warranted revisiting our earlier analysis of the perennial An Odontogenic Example of the genomic/epigenetic controversy, n Genomic/Epigenetic Dichotomy The epigenetic position of the F M H may seem Odontogenesis provides a comprehensible ex- quixotic when molecular genetics is the premier ample. The widespread diagnostic use of vertebrate ontogenetic research paradigm. Indeed, most clini- dental coronal morphology in zoological systemat- cians and experimentalistsn-14--there are excep- ics, vertebrate paleontology, physical anthropology, tions J~5 subscribe to the two epigraphs above, stated and forensic odontology suggests to many a rigid more succinctly as "genes make us, body and mind. ''16 genomic control of odontogenesis, as reflected in From the Department of Anatomy and Cell Biology, College of Physicians the temporally sequential, and spatially restricted, and Surgeons, and School of Dental and Oral Surgery, Columbia Univer- sity. expression of the genomically regulated production Reprint requests to: Prof. Emeritus Melvin L. Moss, Department of of specific molecules as exhibited, for example, in Anatomyand CellBiology,ColumbiaUniversity,630 W. 168th.St., New murine molar development. 43 York, NY 10032.e-mail:moss@civil.eolumbia.edu Copyright© 1997by the AmericanAssociationof Orthodontists. Nevertheless, data exist strongly supportive of 0889-5406/97/$5.00 + 0 8/1/79952 epigenetic regulation of odontogenesis. For exam- 338
  • 12. American Journal of Orthodontics and Dentofacial Orthopedics Moss 339 Volume 112, No. 3 ple, Chiclid fish are polyphyodont (have continu- with the empirical data of animal breeders, it earlier ously replacing dental sets) and can exhibit pro- provided a theoretical basis for certain human eu- nounced dental phenotypic plasticity.44 When the genic theories proposing reproductive inhibition for fish are fed on hard-shelled mollusks, the replacing individuals with "undesirable and genetically (chro- teeth are large and molariform, but when soft mosomally) regulated" medical and social condi- food is fed, those teeth are gracile, conical, and tions: a policy that eventually reached historical nonmolariform. Experimentally in aquaria, the two genocidal depths. 56,57 phenotypic states may be repeatedly and arbitrarily Later, the blending of the classical chromosomal alternated in succeeding dental generations by alter- and vertebrate paleontological disciplines created nately changing the diet's consistency. Because each the neo-Darwinian synthesis, a currently accepted dental replacement cycle involves identical odonto- paradigm of phylogenetic regulation. 58 genic stages, it is postulated that (1) mechanical Recently, molecular (gene) genetics extended forces, related to differential diet "hardness," gen- the claims of the thesis to the regulation of all aspects erate epigenetic signals, mechanotransductively pro- of ontogeny (i.e., of "growth and development"). cessed by dental papilla cellsg.l°; and (2) these The mega-human genome project, 59,6°~61called "the signals control at least the temporal and spatial ultimate triumph of genetics, ''4s explicitly intends to: expression of genomic products related to the de- (1) describe the complete human genome; (2) dem- velopment of differential tooth form, such as size onstrate genomic controls of all developmental pro- and shape. 45-47 cesses, at all structural levels, from the subcellular to If the epigenetic/genomic dichotomy of odonto- the organismal; and, (3) in a societal context, possi- genetic regulation is unresolved, how much more so bly lead to some type of neoeugenics. the complex topic of cephalic morphogenesis where, Many human activities now are claimed to be parenthetically, mechanical loadings also play a genomically regulated: e.g., psychological behav- significant regulatory role. 15 ior6Z; personality63; alcohol and drug abuse64; chro- nobiological cyclic behaviors65; smoking, obesity, The Genomic Thesis alcoholism, drug abuse, food-binging--indeed any The genomic thesis holds that the genome, from attention-deficiency disorder, 66 among many others. the moment of fertilization, contains all the infor- The further suggestion of genomic control of intel- mation necessary to regulate (cause, control, direct) ligence generates prodigious, biomedical contro- (1) the intranuclear formation and transcription of versy in the social sciences and politics. 67 And note mRNA and (2) importantly, without the later addi- the frequent popular press reports of the "discov- tion of any other information, to regulate also all of ery" of yet another "gene" that "controls" yet an- the intracellular and intercellular processes of sub- other developmental, physiological, psychological, sequent, and structurally more complex, cell, tissue, or sociological event, process, or state. organ, and organismal morphogenesisa'2,48: suc- The Biologic Bases for the Genomic Thesis cinctly, "all (phenotype) features are ultimately de- termined by the DNA sequence of the genome. ''49 While comprehensively considered else- In this thesis, morphogenesis is but the prede- brief review is useful. The somatic w h e r e , 48,49,53 a termined reading-out of an intrinsic and inherited cells of an individual metazoan inherit two classes of genomic organismal blueprint 48'49'5°'51'52 where, in molecular information: (1) an identical diploid addition to molecular synthesis, the genome also DNA and (2) the maternal cytoplasmic constituents regulates the geometric attributes of cell, tissue, of the egg: e.g., mitochondria, cytoskeleton, mem- organ, and organismal size, shape, and location. For branes. Only approximately 10% of the genome example, "specific patterns of gene regulation seems related to phenotypic ontogenesis, whereas (cause, control, regulate, determine) the mecha- the human genome has approximately 100,000 nisms by which a fertilized egg divides and genes, "well over 90% ... does not encode precur- progresses through the various decision points to sors to mRNAs or any other RNA. ''53 With regard yield groups of cells that are first determined to to individual phenotypic structural attributes, while become and then actually differentiate to become all somatic cells commonly share approximately specialized tissues of the right dimension and in the 5000 different polypeptide chains, each specific cell proper location. ''s3 type is characterized only by approximately 100 The genomic thesis originated with classical specific proteins. And it is claimed that "these (chromosomal) Mendelian genetics, s4,55 Combined quantitative (protein) differences are related to dif-
  • 13. 340 Moss American Journal of Orthodontics and Dentofacial Orthopedics September 1997 ferences in cell size, shape and internal architec- craniofacial development is controlled by two inter- ture. ''s3 related, temporally sequential, processes: (1) initial The encoding 10% of the DNA exists in two regulatory (homeobox) gene activity and (2) subse- families; the vastly preponderant "housekeeping" quent activity of two regulatory molecular groups: genes and the nonabundant "structural" genes. The growth factor families and steroid/thyroid/retinoic former regulate the normal molecular synthesis of acid super-family. For example, "homeobox genes agents involved in (1) the common energetic (met- coordinate the development of complex craniofacial abolic, respiratory) activities of all cells and, (2) the structures" and in "both normal and abnormal de- specific activities of special cell types (e.g., neurons, velopment, much of the regulation of the develop- osteoblasts, ameloblasts etc.). 52,68 ment of virtually all of the skeletal and connective These genes also regulate the synthesis of the tissue of the face is dependent on a cascade of specific molecular gene products, whose presence, overlapping activity of homeobox genes. ''12 absence, or abnormal molecular configuration are It is claimed that regulatory molecules can (1) associated with the (human) pathologic conditions "alter the manner in which homeobox genes coor- said to have a unitary genetic cause--the so-called dinate cell migration and subsequent cell interac- Mendelian disorders and the "single-gene disorders tions that regulate growth" and (2) be involved in with nonclassic inheritance, ''52 such as Marfan syn- the "genetic variations causing, or contributing to, drome, achondroplasia, osteogenesis imperfecta, the abnormal development of relatively common and Duchenne muscular dystrophy, among many craniofacial malformations . . . perhaps modifying others. 52 For some, such "disorders provide the Hox gene activity. ''52 model on which the program of medical genetics is Specific orthodontic implications of the genomic built. ''59 In such conditions the absence of a normal thesis include claims that "poorly coordination- type, or the presence of a structurally abnormal ordinated control of form and size of structures, or type, of a specific biochemical or molecular struc- groups of structures (e.g., teeth and jaws) by regu- tural entity is sufficient to initiate the cascade of lator genes should do much to explain the very subsequent abnormal developmental pathways, frequent mismatches found in malocclusions and eventuating in a specific pathological state. other dentofacial deformities." And "single regula- A physical analogy is the construction of a tory (homeobox) genes can control the development building wall where either the proportions of the of complex structures.., indicating that single genes concrete are incorrect or an insufficient number of can determine the morphology of at least some metal reinforcing rods are used. In both cases, complex structures," including "how characteristic eventual structural collapse is possible. Substitution noses or jaws are inherited from generation to of intercellular proteoglycans, and of collagen generation. ''s2 fibrils, provides a corresponding skeletal tissue anal- ogy. Here, alterations in the genomically regulated Critical Definitions processes of molecular synthesis can produce an Clarification of this dichotomy is assisted by eventual "structural collapse" at the hierarchically defining the present use of four terms: epigenetics, higher level of a macroscopic bone. Anticipating an hierarchy, emergence, and causation. antithesis, note here that the claim of genomic Epigenetics. Several millennia ago epigenesis de- control of the molecular syntheses underlying the scribed the process(es) by which increasing struc- formation of such elemental (molecular) skeletal tural complexity gradually arose from an originally tissue "building blocks" does not substantiate the unstructured mass, for example the stages of in vivo further claim that the genome regulates the growth chick development or the gradual appearance of a and development (the size, shape, location and histo- pattern during weaving on a loom. 7s-81 Over time, logical composition) of the gross anatomical bone. many alternate, often differing, definitions ap- peared. 22,82 Earlier, they were macroscopic in scale The Genomic Thesis in Orofacial Biology and considered only the extrinsic, extraorganismal There is extensive support for the genomic thesis environment, such as food, light, temperature, and in the orofacial biology literature, with most genetic radiations. 83 Nineteenth century physiology added studies of cephalic or cranial morphogenesis explic- the intrinsic, intraorganismal milieu interieur, s4 such itly or implicitly assuming genomic regulation of as hormones, blood gases, nutrients, and ions. each anatomical structure. 69-77 Epigenetics, as defined here, includes (1) all of A characteristic article 12 claims that prenatal the extrinsic (extraorganismal) factors impinging on
  • 14. American Journal of Orthodontics and Dentofacial Orthopedics Moss 341 Volume 112, No. 3 vital structures, including importantly mechanical mandibular angular process of a given 14-year-old loadings and electroelectric states and (2) all of the male? The genomic thesis holds that this process intrinsic (intraorganismal) biophysical, biomechani- was predetermined; i.e, that individual's osteoblastic cal, biochemical, and bioelectric microenvironmen- genome contained, at the moment of fertilization, tal events occurring on, in, and between individual all the information necessary to regulate where, cells, extracellular materials, and cells and extracel- when, for how long, in what direction, in what lular substances. amount, and at what rates, bone formation and Hierarchy. Biological structures are hierarchically remodeling will occur in that individual, given the organized, with structural and functional complexity absence of disease and the presence of the usual and increasing "upward" from the ever-expanding family necessary extrinsic (environmental) factors, such as of subatomic particles to protons, electrons, atoms, adequate nutrition, and the customary normal phys- molecules, subcellular organelles, and on to cells, iological states, such as are presumed to exist in tissues, organs, and organisms. 4s While a genomic physiology's hypothetical normal human. thesis claims that each higher level is achieved by the The antithesis (and the FMH) suggests that predetermined activity of the genomic information, epigenetic stimuli, created by operations of related an epigenetic antithesis suggests that hierarchical functional matrices and their skeletal unit adaptive complexity results from the functioning of epi- responses, create the "new" information sequen- genetic processes and mechanisms, 3° as described tially, as mandibular ontogenesis proceeds. 9,1° All in the disciplines of developmental mechanicsy ,86 ontogenesis exhibits developmental "cascades," with self-organization, 87 complexity, and chaos, 88,89,9°,91 multiple branching points where decisions are made among others,--topics considered further in the between alternate developmental pathways. Such following epigenetic antithesis. decisions are not predetermined by encoded genetic Emergence. This phenomenon occurs in all nat- information, but instead are responses to some ural hierarchies. It consists of the appearance, at epigenetic stimulus(i). Hierarchy, emergence, and each successively higher and structurally and/or causation are topics of the greatest significance in operationally more complex level, of new attributes any critique of the genomic hypothesis, because the or properties, not present in the lower levels, whose scope and content of molecular genetics is precisely existence or functions could not in any way be that; it deals with only the molecular level of struc- predicted, even from a complete knowledge of all of tural organization. The genomic hypothesis pro- the attributes and properties of any or all of the poses no pathways from molecules to morphogene- preceding lower organizational levels. 92-94 sis? ° Customarily, in craniofacial literature, the For example, full knowledge of all the attributes existence of two "facts" is stated: (1) that at the and properties of an osteocyte does not permit molecular level, a particular gene (or group of prediction of the attributes and properties of any genes) exists and (2) that at some higher, macro- type of bone tissue. And full knowledge of all scopic level, some clinical state of normal growth attributes and properties of all constituent bone and development or of malformation and/or mal- tissue types does not permit prediction of the form function is observed. Without positing any specific (size and shape), growth, or functions of a macro- mechanisms or processes at each intervening hier- scopic "bone." archical level of the developmental cascade, it is Emergence is not genomically controlled. In- simply stated that fact 1 is the cause of fact 2. For stead, the integrated activities of all the attributes in example, "it is demonstrated that synpolydactyly, an a given hierarchical level self-organize to produce inherited human abnormality of the hands and feet, the next higher level of complexity. In every real is caused [italics mine] by expansions of a polyala- sense, biologic structures "build" themselves; that is, nine stretch in the amino-terminal region of bones do not grow, they are grown. Epigenetic HOXD13. ''97 processes and mechanisms are regulatory (causal) of In the genomic thesis morphogenesis is reduced hierarchical organization and of emergence and to molecular synthesis. self-organization. 95 T h e Classification of C a u s a t i o n 1t Causation. From this vast topic, 96 we consider only how the attributes of a given biologic structural There are four principal causes of ontogenesis: level "cause" (control, regulate, determine) the at- material (with what?), formal (by what rules?), tributes of the next higher level. For example, what efficient (how?), and final (why?). These may be causes osteogenesis on the ectofacial surface the left categorized as either intrinsic (material and formal)
  • 15. 342 Moss American Journal of Orthodontics and Dentofacial Orthopedics September 1997 and extrinsic (efficient); final cause (teleology) is not disks, and papers. The formal cause is the software: considered further. Of importance, both material a specific word processing program, both its appar- and formal causes are classified as prior causes, i.e., ent, user-friend form and, in reality, its ultimate existing before the creation of some specific state or expression in machine language code. No combina- structure. Efficient cause is proximate; i.e., its oper- tion of hardware and software could ever write an ation immediately causes the creation of a new state article. Extrinsic, epigenetic input is required, i.e., or attribute. Material and formal causes are intrinsic the composition and input of the text itself. Both because they reside within vital structure (either intrinsic causes must be present before (prior to) the intracellularly or intercellularly); efficient causes are textual input, whereas the extrinsic, epigenetic typ- extrinsic--they represent the entire spectrum of ing is immediately (i.e., proximately) followed by epigenetic processes, mechanisms, and events capa- creation, on the hard disk, of the text itself. ble of being imposed on vital structures. Both prior (intrinsic) and proximate (extrinsic) In biology, material cause is represented by all causes are necessary causes; neither alone is a the levels of cellular and intercellular materials, sufficient cause for the creation of this manuscript. without reference to any specific structural (anatom- Only the two integrated together furnish the neces- ical) arrangement. Formal cause is the genomic sary and sufficient cause. code, i.e., a series of "rules" or "laws." These act at In ontogenesis, genomic (intrinsic, prior) and the at the molecular level to regulate the initial epigenetic (extrinsic, proximate) factors are each a creation of the constituents of material cause. Effi- necessary cause, but neither alone is a sufficient cient cause(s) are the epigenetic factors, as defined cause. Only the interaction of both provides both above, whose actions immediately regulate the next the necessary and sufficient cause of morphogene- developmental branching point. sisJ 1 This conclusion foreshadows the resolving A metaphor is helpful. Consider the use of a synthesis of this dichotomy, presented in the com- computer to prepare this manuscript. The material panion article, which also contains the comprehen- cause is the hardware: the computers, printers, sive bibliography. AVAILABILITY OF JOURNAL BACK ISSUES As a service to our subscribers, copies of back issues of the American Journal of Orthodontics and Dentofacial Orthopedics for the preceding 5 years are maintained and are available for purchase from the publisher, Mosby-Year Book, Inc., at a cost of $11.00 per issue. The following quantity discounts are available: 25% off on quantities of 12 to 23, and one third off on quantities of 24 or more. Please write to Mosby-Year Book, Inc., Subscription Services, 11830 Westline Industrial Dr., St. Louis, MO 63146-3318, or call (800)453-4351 or (314)453-4351 for information on availability of particular issues. If unavailable from the publisher, photocopies of complete issues are available from University Microfilms International, 300 N. Zeeb Rd., Ann Arbor, MI 48106 (313)761-4700.