Marked Disturbance of Calcium Homeostasis in Mice With Targeted Disruption of the Trpv6 Calcium Channel Gene

Abstract

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.