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The vitamin D analog ZK191784 normalizes decreased bone matrix mineralization in mice lacking the calcium channel
Bram C J van der Eerden1, Nadja Fratzl-Zelman, Tom Nijenhuis
1Department of Internal Medicine, Erasmus Medical Centre Rotterdam, Rotterdam, The Netherlands. b.vandereerden@erasmusmc.nl
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.
Insights
Vitamin D receptor antagonist ZK191784 partially restored bone mineralization and thickness in mice lacking TRPV5. This highlights the importance of vitamin D in bone formation and calcium homeostasis.
Area of Science:
- Endocrinology
- Nephrology
- Bone Biology
Background:
- Mice lacking TRPV5 (TRPV5(-/-)) exhibit impaired renal calcium reabsorption and secondary hypervitaminosis D.
- Previous studies showed ZK191784 is an intestine-specific 1,25(OH)2D3 antagonist but acts as a kidney agonist, with ambiguous bone effects.
- The role of vitamin D receptor (VDR) antagonists in bone health, particularly in calcium homeostasis disorders, requires further investigation.
Purpose of the Study:
- To evaluate the effect of the VDR antagonist ZK191784 on murine bone in TRPV5 knockout mice.
- To investigate the impact of ZK191784 on bone matrix mineralization and gene expression in the context of altered calcium metabolism.
Main Methods:
- Treatment of 8-week-old female Trpv5(+/+) and Trpv5(-/-) mice with ZK191784 (50 µg/kg/day) or vehicle for 4 weeks.
- Quantitative backscattered electron imaging to assess bone matrix mineralization and trabecular bone thickness.
- Analysis of bone gene expression, including 1α-hydroxylase (Cyp27b1) and 24-hydroxylase (Cyp24a1), and serum phosphate and FGF23 levels.
Main Results:
- ZK191784 treatment partially restored reduced bone matrix mineralization and trabecular bone thickness in Trpv5(-/-) mice.
- Bone gene expression showed upregulated Cyp27b1 and downregulated Cyp24a1 in ZK191784-treated Trpv5(-/-) mice, indicating local VDR resistance.
- Phosphate homeostasis remained unaffected, with unaltered serum PO4(3-), FGF23, and Fgf23 mRNA expression.
Conclusions:
- Circulating 1,25(OH)2D3 is crucial for maintaining calcium homeostasis and supporting optimal bone formation and matrix mineralization.
- ZK191784 demonstrates a partial restorative effect on bone mineralization in TRPV5-deficient mice, suggesting a complex role in VDR signaling.
- The findings underscore the intricate relationship between calcium balance, vitamin D, and skeletal health.
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