Marked disturbance of calcium homeostasis in mice with targeted disruption of the Trpv6 calcium channel gene

TY - JOUR

T1 - Marked disturbance of calcium homeostasis in mice with targeted disruption of the Trpv6 calcium channel gene

AU - Bianco, Suzy D C

AU - Peng, Ji Bin

AU - Takanaga, Hitomi

AU - Suzuki, Yoshiro

AU - Crescenzi, Alessandra

AU - Kos, Claudine H.

AU - Zhuang, Liyan

AU - Freeman, Michael R.

AU - Gouveia, Cecilia H A

AU - Wu, Jiangping

AU - Luo, Hongyu

AU - Mauro, Theodora

AU - Brown, Edward M.

AU - Hediger, Matthias A.

PY - 2007/2/1

Y1 - 2007/2/1

N2 - We report the phenotype of mice with targeted disruption of the Trpv6 (Trpv6 KO) epithelial calcium channel. The mice exhibit disordered Ca 2+ 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 Ca 2+-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.

AB - We report the phenotype of mice with targeted disruption of the Trpv6 (Trpv6 KO) epithelial calcium channel. The mice exhibit disordered Ca 2+ 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 Ca 2+-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.

KW - Alopecia

KW - Intestinal calcium absorption

KW - Renal excretion

KW - TRPV6

KW - Vitamin D

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UR - http://www.scopus.com/inward/citedby.url?scp=33846505390&partnerID=8YFLogxK

U2 - 10.1359/jbmr.061110

DO - 10.1359/jbmr.061110

M3 - Article

C2 - 17129178

AN - SCOPUS:33846505390

VL - 22

SP - 274

EP - 285

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

IS - 2

ER -