The authors state that they have no conflicts of interest.
Marked Disturbance of Calcium Homeostasis in Mice With Targeted Disruption of the Trpv6 Calcium Channel Gene†
Article first published online: 13 NOV 2006
Copyright © 2007 ASBMR
Journal of Bone and Mineral Research
Volume 22, Issue 2, pages 274–285, February 2007
How to Cite
Bianco, S. D., Peng, J.-B., Takanaga, H., Suzuki, Y., Crescenzi, A., Kos, C. H., Zhuang, L., Freeman, M. R., Gouveia, C. H., Wu, J., Luo, H., Mauro, T., Brown, E. M. and Hediger, M. A. (2007), Marked Disturbance of Calcium Homeostasis in Mice With Targeted Disruption of the Trpv6 Calcium Channel Gene. J Bone Miner Res, 22: 274–285. doi: 10.1359/jbmr.061110
- Issue published online: 4 DEC 2009
- Article first published online: 13 NOV 2006
- Manuscript Accepted: 7 NOV 2006
- Manuscript Revised: 11 OCT 2006
- Manuscript Received: 15 AUG 2006
- intestinal calcium absorption;
- renal excretion;
- vitamin D
We report the phenotype of mice with targeted disruption of the Trpv6 (Trpv6 KO) epithelial calcium channel. The mice exhibit disordered Ca2+ homeostasis, including defective intestinal Ca2+ absorption, increased urinary Ca2+ excretion, decreased BMD, deficient weight gain, and reduced fertility. Although our Trpv6 KO affects the closely adjacent EphB6 gene, the phenotype reported here is not related to EphB6 dysfunction.
Introduction: The mechanisms underlying intestinal Ca2+ absorption are crucial for overall Ca2+ homeostasis, because diet is the only source of all new Ca2+ in the body. Trpv6 encodes a Ca2+-permeable cation channel responsible for vitamin D–dependent intestinal Ca2+ absorption. Trpv6 is expressed in the intestine and also in the skin, placenta, kidney, and exocrine organs.
Materials and Methods: To determine the in vivo function of TRPV6, we generated mice with targeted disruption of the Trpv6 (Trpv6 KO) gene.
Results: Trpv6 KO mice are viable but exhibit disordered Ca2+ homeostasis, including a 60% decrease in intestinal Ca2+ absorption, deficient weight gain, decreased BMD, and reduced fertility. When kept on a regular (1% Ca2+) diet, Trpv6 KO mice have deficient intestinal Ca2+ absorption, despite elevated levels of serum PTH (3.8-fold) and 1,25-dihydroxyvitamin D (2.4-fold). They also have decreased urinary osmolality and increased Ca2+ excretion. Their serum Ca2+ is normal, but when challenged with a low (0.25%) Ca2+ diet, Trpv6 KO mice fail to further increase serum PTH and vitamin D, ultimately developing hypocalcemia. Trpv6 KO mice have normal urinary deoxypyridinoline excretion, although exhibiting a 9.3% reduction in femoral mineral density at 2 months of age, which is not restored by treatment for 1 month with a high (2%) Ca2+ “rescue” diet. In addition to their deranged Ca2+ homeostasis, the skin of Trpv6 KO mice has fewer and thinner layers of stratum corneum, decreased total Ca2+ content, and loss of the normal Ca2+ gradient. Twenty percent of all Trpv6 KO animals develop alopecia and dermatitis.
Conclusions: Trpv6 KO mice exhibit an array of abnormalities in multiple tissues/organs. At least some of these are caused by tissue-specific mechanisms. In addition, the kidneys and bones of Trpv6 KO mice do not respond to their elevated levels of PTH and 1,25-dihydroxyvitamin D. These data indicate that the TRPV6 channel plays an important role in Ca2+ homeostasis and in other tissues not directly involved in this process.