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

Area of Science:

• Molecular Biology
• Genetics
• Bone Biology
• Cell Physiology

Background:

• Mutations in the ClC-7 (2Cl(-)/1H(+)-exchanger) cause osteopetrosis by impairing osteoclast function.
• The precise reduction threshold of ClC-7 function that becomes rate-limiting for bone resorption remains unclear.
• Disease severity in patients with osteopetrosis due to ClC-7 mutations does not correlate with mutated protein expression levels.

Purpose of the Study:

• To determine the extent to which ClC-7 function reduction limits bone resorption.
• To investigate the impact of varying ClC-7 expression levels on osteoclast activity and bone mass.
• To explore the role of ClC-7 in gastric acid secretion and its relation to osteopetrorickets.

Main Methods:

• Generation of transgenic mice with varying ClC-7 expression levels in osteoclasts.
• Crossbreeding transgenic mice with Clcn7(-/-) mutants to rescue osteopetrotic phenotypes.
• Analysis of bone structure, osteoblast function, osteoclast differentiation, and gastric pH in mutant mice.

Main Results:

• A specific double transgenic mouse line mimicked human autosomal dominant osteopetrosis.
• Reduced ClC-7 expression (20-30% of wild-type) impaired osteoclast resorptive activity and increased osteoclast numbers, size, and nuclei.
• A ~70% reduction in ClC-7 function was sufficient to increase bone mass but did not enhance bone formation or significantly alter gastric pH.

Conclusions:

• Approximately 70% reduction in ClC-7 function is sufficient to cause osteopetrosis by impairing osteoclast resorption.
• Reduced ClC-7 function does not necessarily enhance bone formation, suggesting uncoupled bone remodeling.
• ClC-7 is not critically involved in gastric acid secretion, explaining the absence of osteopetrorickets in CLCN7-related osteopetrosis.