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ClC-7 expression levels critically regulate bone turnover, but not gastric acid secretion

Item Type:Article
Title:ClC-7 expression levels critically regulate bone turnover, but not gastric acid secretion
Creators Name:Supanchart, C. and Wartosch, L. and Schlack, C. and Kühnisch, J. and Giehl, M. and Felsenberg, D. and Fuhrmann, J.C. and de Vernejoul, M.C. and Jentsch, T.J. and Kornak, U.
Abstract:Mutations in the 2Cl(-)/1H(+)-exchanger ClC-7 impair osteoclast function and cause different types of osteoclast-rich osteopetrosis. However, it is unknown to what extent ClC-7 function has to be reduced to become rate-limiting for bone resorption. In osteoclasts from osteopetrosis patients expression of the mutated ClC-7 protein did not correlate with disease severity and resorption impairment. Therefore, a series of transgenic mice expressing ClC-7 in osteoclasts at different levels was generated. Crossing of these mice with Clcn7(-/-) mutants rescued the osteopetrotic phenotype to variable degrees. One resulting double transgenic line mimicked human autosomal dominant osteopetrosis. The trabecular bone of these mice showed a reduction of osteoblast numbers, osteoid, and osteoblast marker gene expression indicative of reduced osteoblast function. In osteoclasts from these mutants ClC-7 expression levels were 20 to 30% of wildtype levels. These reduced levels not only impaired resorptive activity, but also increased numbers, size and nucleus numbers of osteoclasts differentiated in vitro. Although ClC-7 was expressed in the stomach and PTH levels were high in Clcn7(-/-) mutants loss of ClC-7 did not entail a relevant elevation of gastric pH. In conclusion, we show that in our model a reduction of ClC-7 function by approximately 70% is sufficient to increase bone mass, but does not necessarily enhance bone formation. ClC-7 does not appear to be crucially involved in gastric acid secretion, which explains the absence of an osteopetrorickets phenotype in CLCN7-related osteopetrosis.
Keywords:Osteopetrosis, Rickets, Osteoclast, Calcium Homeostasis, Proton Secretion, Chloride Channel, Osteoclast-Osteoblast Coupling, Animals, Mice
Page Range:92-102
Date:January 2014
Official Publication:https://doi.org/10.1016/j.bone.2013.09.022
PubMed:View item in PubMed

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