The epithelial Ca2+ channel TRPV5 is essential for proper osteoclastic bone resorption.
Bone remodeling involves the interplay of bone resorption and formation and is accurately controlled to maintain bone mass. Both processes require transcellular Ca(2+) transport, but the molecular mechanisms engaged remain largely elusive. The epithelial Ca(2+) channel TRPV5 is one of the most Ca(2+)-selective transient receptor potential (TRP) channels. In this study, the functional role of TRPV5 in bone was investigated. TRPV5 mRNA was expressed in human and murine bone samples and in osteoclasts along with other genes involved in transcellular Ca(2+) transport, including calbindin-D(9K) and calbindin-D(28K), Na(+)/Ca(2+) exchanger 1, and plasma membrane Ca(2+)-ATPase 1b. TRPV5 expression in murine osteoclasts was confirmed by immunostaining and showed predominant localization to the ruffled border membrane. However, TRPV5 was absent in osteoblasts. Analyses of femoral bone sections from TRPV5 knockout (TRPV5(-/-)) mice revealed increased osteoclast numbers and osteoclast area, whereas the urinary bone resorption marker deoxypyridinoline was reduced compared with WT (TRPV5(+/+)) mice. In an in vitro bone marrow culture system, the amount of osteoclasts and number of nuclei per osteoclast were significantly elevated in TRPV5(-/-) compared with TRPV5(+/+) mice. However, using a functional resorption pit assay, we found that bone resorption was nearly absent in osteoclast cultures from TRPV5(-/-) mice, supporting the impaired resorption observed in vivo. In conclusion, TRPV5 deficiency leads to an increase in osteoclast size and number, in which Ca(2+) resorption is nonfunctional. This report identifies TRPV5 as an epithelial Ca(2+) channel that is essential for osteoclastic bone resorption and demonstrates the significance of transcellular Ca(2+) transport in osteoclastic function.
van der Eerden
Bram C J
BC
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
Hoenderop
Joost G J
JG
de Vries
Teun J
TJ
Schoenmaker
Ton
T
Buurman
Cok J
CJ
Uitterlinden
André G
AG
Pols
Huibert A P
HA
Bindels
René J M
RJ
van Leeuwen
Johannes P T M
JP
D000135:Acid Phosphatase; D000596:Amino Acids / Q000652:urine; D000818:Animals; D001862:Bone Resorption / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics* / Q000378:metabolism*; D017931:DNA Primers; D005270:Femur Head / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000235:genetics* / Q000378:metabolism*; D000071681:Tartrate-Resistant Acid Phosphatase
D000596:Amino Acids; D015220:Calcium Channels; D017931:DNA Primers; D007527:Isoenzymes; D012333:RNA, Messenger; D050916:TRPV Cation Channels; C492239:TRPV5 protein, human; C036020:deoxypyridinoline; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D002118:Calcium