title: The vitamin D analog ZK191784 normalizes decreased bone matrix mineralization in mice lacking the calcium channel TRPV5.
abstract: Mice lacking the renal epithelial Ca(2+) channel TRPV5 (TRPV5(-/-)) display impaired renal Ca(2+) reabsorption, hypercalciuria, and intestinal Ca(2+) hyperabsorption, due to secondary hypervitaminosis D. Using these mice, we previously demonstrated that ZK191784 acts as an intestine-specific 1,25(OH)(2) D(3) antagonist without affecting serum calcium levels. On the other hand, it acted as an agonist in the kidney and the effects of ZK191784 on bone were ambiguous. The present study was undertaken to further evaluate the effect of the vitamin D receptor antagonist on murine bone in mice lacking TRPV5. Eight-week-old female Trpv5(+/+) and Trpv5(-/-) mice were treated for 4 weeks with or without 50 µg/kg/day ZK191784. Quantitative backscattered electron imaging showed that the reduced bone matrix mineralization found in femoral bones of Trpv5(-/-) mice was partially but significantly restored upon ZK191784 treatment, just as we observed for trabecular bone thickness. This supports the significance of 1,25(OH)(2) D(3) and optimal control of Ca(2+) homeostasis for bone formation and matrix mineralization. Restoration also took place at the bone gene expression level, where 1α-hydroxylase (Cyp27b1) mRNA in femurs from ZK-treated Trpv5(-/-) mice was upregulated compared to control levels. The downregulated 24-hydroxylase (Cyp24a1) gene expression in femoral bone indicated local vitamin D resistance in the mice treated with ZK191784. Phosphate homeostasis was unaffected between the groups as shown by unaltered serum PO(4)(3-) and fibroblast growth factor (FGF) 23 as well as Fgf23 mRNA expression in bone. In conclusion, circulating 1,25(OH)(2) D(3) is important for optimal control of Ca(2+) homeostasis but also for controlled bone formation and matrix mineralization.
authors: Department of Internal Medicine, Erasmus Medical Centre Rotterdam, Rotterdam, The Netherlands. b.vandereerden@erasmusmc.nl
authors: Bram C J
authors: BC
authors: van der Eerden
authors: Nadja
authors: N
authors: Fratzl-Zelman
authors: Tom
authors: T
authors: Nijenhuis
authors: Paul
authors: P
authors: Roschger
authors: Ulrich
authors: U
authors: Zügel
authors: Andreas
authors: A
authors: Steinmeyer
authors: Joost G J
authors: JG
authors: Hoenderop
authors: René J M
authors: RJ
authors: Bindels
authors: Klaus
authors: K
authors: Klaushofer
authors: Johannes P T M
authors: JP
authors: van Leeuwen
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000096:biosynthesis; D000818:Animals; D001857:Bone Matrix / Q000187:drug effects*; D002113:Calcification, Physiologic / Q000187:drug effects*; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000172:deficiency*; D002762:Cholecalciferol / Q000097:blood / Q000378:metabolism; D005260:Female; D005269:Femur / Q000187:drug effects; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D051379:Mice; D010710:Phosphates / Q000097:blood; D013250:Steroid Hydroxylases / Q000096:biosynthesis; D050916:TRPV Cation Channels / Q000172:deficiency*; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D015220:Calcium Channels; C000717428:Fgf23 protein, mouse; D010710:Phosphates; D050916:TRPV Cation Channels; C492240:Trpv5 protein, mouse; C470666:ZK 191784; D014807:Vitamin D; D002762:Cholecalciferol; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D013250:Steroid Hydroxylases; C585550:Cyp24a1 protein, mouse; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D002118:Calcium