1. Université Hassan II-Mohammedia-Casablanca FACULTE DES SCIENCES BEN M’SIK METABOLISME PHOSPHOCALCIQUE : REGULATION ET DESORDRES Module : Physiopathologie Humaine II Master : BIOLOGIE ET SANTE 2009-2010 Pr. El Hassane TAHRI

6. Concentrations en Calcium et en phosphates de : l’eau de mer, l’eau douce, certaines vertébrés et un invertébré Calcium total (mg/l) Calcium ionisé (mg/l) Phos-phates (mg/l) Eau de mer Eau douce 400 36 400 36 0.1 Invertébré marin : Nephrops 478 Vertébrés : Lamproie ( Petromyzon marinus) Requin (carcharhinus) Téléostéen marin (Paralabrax) Mammifères (Homo sapiens) 104 180 128 95 70 124 80 50 39 60 60 30

11. Dans cette partie du cours , on va s’intéresser au : Contrôle et à la régulation de l’homéostasie calcique systémique

12. Les principaux compartiments du calcium et leur taux d’échanges

13. Contenu total de l’organisme humain en Ca, Mg et phosphates

23. Structure de la vitamine D Vitamine D2 ou Ergocalciférol Vitamine D3 ou Cholécalciférol

28. Sources les plus riches de vitamine D (en UI pour 100g - 1 UI = 0,025 µg ) Huile de foie de morue Hareng cru Saumon Sardines en boîte Thon en boîte Céréales Oeufs de poule Beurre Foie de boeuf Foie de veau Lait 3 400 900 500 300 230 50 40 30 19 14 4 - 8

29. Apports quotidiens conseillés en vitamine D (1 UI = 0,025 µg) Prématurés Nourrissons < 6 mois Enfant de 6 à 12 mois Enfant de 1 à 3 ans Enfant de 4 à 9 ans Enfant de 10 à 12 ans Adolescents Adolescentes Homme adulte Femme adulte Femme enceinte Femme allaitantes Personnes âgées 600 UI 400 UI 400-600 UI 400-600 UI 400 UI 400 UI 400 UI 400 UI 400 UI 400 UI 600 UI 800 UI 480 UI

31. Biosynthèse de la vitamine D 1 2 5 6 8 9 3 4 10 11 12 19 14 13 16 17 15 18 20 21 22 25 27 26 7-dehydrocholestérol 23 24 7 A B C D

32. Copyright ©2004 The American Society for Nutrition DeLuca, H. F Am J Clin Nutr 2004;80:1689S-1696S Structure of vitamin D3, or cholecalciferol, and its numbering system

33. Biochimie de la vitamine D

36. Production rénale et extrarénale et effets endocrines, autocrines et paracrines du 1,25(OH)2VitD

37. Copyright ©2005 American Physiological Society Dusso, A. S. et al. Am J Physiol Renal Physiol 289: F8-F28 2005; doi:10.1152/ajprenal.00336.2004 Role of 1,25(OH)2D3 in calcium homeostasis

39. Biosynthèse de la Vitamine D 25OHD3 et 1,25(OH)2D3 C25 C25 C1

51. Contrôle de la production des métabolites de la vitD 1. Facteurs agissant directement sur la cellule rénale Activateurs : Hormone parathyroïdienne Calcitonine Prostaglandines (PGE2 et PGF2a) AMPc Prolactine Inhibiteurs : 25OHD3 24,25 (OH)2D3 1,25(OH)2D3 Calcium Phosphore 2. Facteurs agissant de façon vraisemblablement indirecte Activateurs : Insuline Hormone de croissance, IGF-1 Oestradiol Hypocalcémie Hypophosphatémie Inhibiteurs : Thyroxine Strontium Diphosphonates (forte dose) Acide maléique Acidose chronique Ethanol ……

53. Rôle de la mégaline et de la IDBP-3 ( Intracellular Vitamin D Binding Protein 3 ) dans la 1 α - hydroxylation du 25(OH)D3

56. Structure générale des récepteurs de la superfamille des récepteurs nucléaires

57. Les domaines fonctionnels du récepteur de la Vitamine D (VDR)

58. Copyright ©2005 American Physiological Society Dusso, A. S. et al. Am J Physiol Renal Physiol 289: F8-F28 2005; doi:10.1152/ajprenal.00336.2004 Current model for the control of vitamin D receptor (VDR)-mediated actions of 1,25(OH)2D3

59. Copyright ©2004 The American Society for Nutrition DeLuca, H. F Am J Clin Nutr 2004;80:1689S-1696S Diagrammatic representation of the known molecular events in the regulation of gene expression by the vitamin D hormone, 1,25(OH)2D3, acting through its receptor, VDR

60. Les différentes familles de récepteurs nucléaires et leurs éléments de réponse (HRE)

61. Eléments de réponses (VDRE) de quelques gènes cibles

62. Distribution tissulaire et cellulaire du récepteur du 1,25(OH)2D3 Fonction Tissus Types cellulaires Métab. Phosphocalcique Intestin Cellules Epithéliales Os Cartilage Rein Ostéoblastes Chondrocyte Epithélium (TCD) Endocrine Parathyroïdes Pancréas Hypophyse Thyroïde Cellules principales Cellules B Cellules somatotrophes Cellules C Reproduction Testicules Glandes mammaires Placenta Utérus Sertoli/tube séminifère Epithélium ? ? Autres Peau Muscle Parotides Cerveau Thymus Moelle osseuse Cellules cancéreuses Epiderme Myocyte , myoblaste embryonnaire Cellules acinales Hippocampe, neurones Lymphocytes T Monocytes, lymphocytes T activés Carcinome : Vessie, Glande mammaire, Thyroïde médullaire); Fibrosarcome, Adénsarcome pancréatique, adénome pituitaire

63. RAPID NONGENOMIC ACTIONS OF 1,25(OH)2D3 (Dusso, A. S. et al. Am J Physiol Renal Physiol 289: F8-F28 2005) Vitamin D compounds, like other steroid hormones, can also elicit responses that are too rapid to involve changes in gene expression and appear to be mediated by cell surface receptors. The role of the nongenomic actions in most cells remains uncertain. In the chick duodenum, 1,25(OH)2D3 stimulates vesicular calcium movement from the lumen to the basolateral surface within minutes ( 180 ), but the overall contribution of this pathway is not clear. 1,25(OH)2D3 can rapidly stimulate phosphoinositide metabolism ( 32 , 153 , 170 ), cytosolic calcium levels ( 116 , 152 , 159 , 170 , 228 ), cGMP levels ( 98 , 245 ), PKC ( 230 ), MAP kinases ( 21 , 222 ), and the opening of chloride channels ( 260 ). In chondrocytes, nongenomic actions of both 1,25(OH)2D3 and 24,25(OH)2D3 alter membrane lipid turnover, prostaglandin production, and protease activity that leads to modification of bone matrix and calcification ( 33 ). The nature of the receptor that mediates the rapid actions remains controversial. At least two distinct receptors have been identified. The better characterized is the membrane-associated, rapid-response steroid-binding protein (1,25D3-MARRS) isolated from chick intestinal basolateral membranes on the basis of 1,25(OH)2D3 binding ( 177 ). Antibodies to the NH2-terminal domain of 1,25D3-MARRS blocked the nongenomic actions of 1,25(OH)2D3 ( 179 ). 1,25D3-MARRS has now been found to be identical to the protein thiol-dependent oxidoreductase ERp57 ( 178 ), which plays a role in glycoprotein folding through the formation of disulfide bonds and acts as part of a chaperone complex with calreticulin and calnexin ( 78 ). ERp57 ribozyme knockdown reduced membrane binding of 1,25(OH)2D3 and rapid responses ( 178 ), but how this enzyme mediates the rapid actions of 1,25(OH)2D3 remains to be determined. Another 1,25(OH)2D3-binding protein, annexin II, was identified in the plasma membranes of ROS 24/1 rat osteosarcoma cells that do not express the VDR ( 14 ). Polyclonal antibodies to annexin II decreased binding of 1,25(OH)2-[14C]D3 and blocked the increase in cytosolic calcium by 1,25(OH)2D3 ( 16 ). However, a recent report could not reproduce the 1,25(OH)2D3 binding to annexin II ( 168 ). The rapid actions of 24,25(OH)2D3 in chondrocytes appear to be mediated by a receptor distinct from those for 1,25(OH)2D3, although its identity is not known. Several studies have indicated that the rapid actions of 1,25(OH)2D3 require the presence of the VDR. The apparent nongenomic actions of 1,25(OH)2D3 are absent in cells isolated from VDR-null mice ( 81 , 261 ), and it has been proposed that the VDR mediates these rapid effects. Furthermore, the VDR was recently found to be present in caveolae-enriched plasma membrane fractions ( 121 ). However, the ligand specificities of the VDR and the rapid action receptor are very different ( 29 , 182 , 263 ), and 1,25(OH)2D3 cannot stimulate transcaltachia in vitamin D-deficient chick duodenum. This would suggest that the VDR is required for the expression of gene products involved in the rapid, nongenomic response. The exact role of the VDR in the rapid actions remains to be clarified. Nongenomic events have been proposed to modulate the genomic actions of 1,25(OH)2D3 ( 15 , 17 , 85 ), but this remains controversial. Numerous studies have presented evidence that the nongenomic actions may not be critical for 1,25(OH)2D3-mediated gene activation ( 84 , 127 , 134 , 135 , 181 , 264 ) or inhibition of cell proliferation ( 105 , 181 ). However, nongenomic stimulation of protein kinases could potentially influence the VDR-mediated effects of 1,25(OH)2D3.

69. PTH : Précurseurs et produits de clivages