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

• Published in: Bone (New York, N.Y.) Vol. 58; pp. 92 - 102
• Main Authors: Supanchart, C, Wartosch, L, Schlack, C, Kühnisch, J, Felsenberg, D, Fuhrmann, J.C, de Vernejoul, M.-C, Jentsch, T.J, Kornak, U
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01-01-2014; Elsevier
• Subjects: Animals; Biological and medical sciences; Bone Remodeling; Bone Resorption - complications; Bone Resorption - genetics; Bone Resorption - pathology; Bone Resorption - physiopathology; Calcium - metabolism; Calcium homeostasis; Cell Count; Cell Differentiation - genetics; Cell Fusion; Chloride channel; Chloride Channels - deficiency; Chloride Channels - genetics; Chloride Channels - metabolism; Diseases of the osteoarticular system; Fundamental and applied biological sciences. Psychology; Gastric Acid - secretion; Genes, Dominant; Genes, Recessive; Humans; Hydrogen-Ion Concentration; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical sciences; Mice; Mice, Transgenic; Orthopedics; Osteoblasts - metabolism; Osteoblasts - pathology; Osteoclast; Osteoclasts - metabolism; Osteoclasts - pathology; Osteoclast–osteoblast coupling; Osteogenesis - genetics; Osteopetrosis; Osteopetrosis - complications; Osteopetrosis - genetics; Osteopetrosis - pathology; Osteopetrosis - physiopathology; Phenotype; Proton secretion; Skeleton and joints; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: osteoarticular system, musculoskeletal system; Chloride channel; Osteoclast; Osteopetrosis; Osteoclast–osteoblast coupling; Calcium homeostasis; Proton secretion; Stomach; Calcium; Secretion; Diseases of the osteoarticular system; Homeostasis; Bone remodeling; Genetic disease; Regulation(control); Osteoclast―osteoblast coupling; Morphology; Osteoblast; Osteochondrodysplasia
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2013.09.022

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.