title: 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 Ca(2+) homeostasis, including defective intestinal Ca(2+) absorption, increased urinary Ca(2+) 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.
  
  
  BACKGROUND
  The mechanisms underlying intestinal Ca(2+) absorption are crucial for overall Ca(2+) homeostasis, because diet is the only source of all new Ca(2+) in the body. Trpv6 encodes a Ca(2+)-permeable cation channel responsible for vitamin D-dependent intestinal Ca(2+) absorption. Trpv6 is expressed in the intestine and also in the skin, placenta, kidney, and exocrine organs.
  
  
  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 Ca(2+) homeostasis, including a 60% decrease in intestinal Ca(2+) absorption, deficient weight gain, decreased BMD, and reduced fertility. When kept on a regular (1% Ca(2+)) diet, Trpv6 KO mice have deficient intestinal Ca(2+) 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 Ca(2+) excretion. Their serum Ca(2+) is normal, but when challenged with a low (0.25%) Ca(2+) 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%) Ca(2+) "rescue" diet. In addition to their deranged Ca(2+) homeostasis, the skin of Trpv6 KO mice has fewer and thinner layers of stratum corneum, decreased total Ca(2+) content, and loss of the normal Ca(2+) 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 Ca(2+) homeostasis and in other tissues not directly involved in this process.
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Suzy D C
authors.initials: SD
authors.lastname: Bianco
authors.forename: Ji-Bin
authors.initials: JB
authors.lastname: Peng
authors.forename: Hitomi
authors.initials: H
authors.lastname: Takanaga
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Alessandra
authors.initials: A
authors.lastname: Crescenzi
authors.forename: Claudine H
authors.initials: CH
authors.lastname: Kos
authors.forename: Liyan
authors.initials: L
authors.lastname: Zhuang
authors.forename: Michael R
authors.initials: MR
authors.lastname: Freeman
authors.forename: Cecilia H A
authors.initials: CH
authors.lastname: Gouveia
authors.forename: Jiangping
authors.initials: J
authors.lastname: Wu
authors.forename: Hongyu
authors.initials: H
authors.lastname: Luo
authors.forename: Theodora
authors.initials: T
authors.lastname: Mauro
authors.forename: Edward M
authors.initials: EM
authors.lastname: Brown
authors.forename: Matthias A
authors.initials: MA
authors.lastname: Hediger
mesh_terms: D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000502:physiology*; D017931:DNA Primers; D006706:Homeostasis; D007408:Intestinal Absorption; D051379:Mice; D018345:Mice, Knockout; D010281:Parathyroid Hormone / Q000097:blood; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D050916:TRPV Cation Channels / Q000235:genetics / Q000502:physiology*
chemical_list: D015220:Calcium Channels; D017931:DNA Primers; D010281:Parathyroid Hormone; D012333:RNA, Messenger; D050916:TRPV Cation Channels; C446923:Trpv6 protein, mouse; D002118:Calcium