AUTHOR=Chen Xi , Wang Ziyuan , Fu Wenzhen , Wei Zhe , Gu Jiemei , Wang Chun , Zhang Zhenlin , Yu Xiangtian , Hu Weiwei 

TITLE=Metabolomics study of osteopetrosis caused by CLCN7 mutation reveals novel pathway and potential biomarkers

JOURNAL=Frontiers in Endocrinology

VOLUME=15

YEAR=2025

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1418932

DOI=10.3389/fendo.2024.1418932

ISSN=1664-2392

ABSTRACT=<sec><title>Objective</title><p><italic>CLCN7</italic> mutation caused abnormal osteoclasts, resulting in osteopetrosis. Depending on the type of mutation, <italic>CLCN7</italic> mutations can lead to severe or relatively benign forms of osteopetrosis. However, the serum metabolic alterations in osteopetrosis caused by <italic>CLCN7</italic> mutation are still unknown. We aimed to investigate the differences in the metabolome of osteopetrosis patients caused by <italic>CLCN7</italic> mutation versus healthy controls (HC), uncovering potential subtype diagnosis biomarkers.</p></sec><sec><title>Methods</title><p>19 osteopetrosis patients caused by <italic>CLCN7</italic> mutation and 19 HC were recruited for liquid chromatography–tandem mass spectrometry analysis. The screened pathway was validated in the myeloid cell specific <italic>Clcn7<sup>G763R</sup></italic> mutant mouse model by quantitative real-time PCR analysis.</p></sec><sec><title>Results</title><p>Three metabolic pathways were significantly enriched, including glycerophospholipid metabolism (<italic>P</italic>=0.036948), arachidonic acid metabolism (<italic>P</italic>=0.0058585) and linoleic acid metabolism (<italic>P</italic>=0.032035). Ten differential expressed metabolites were located in these three pathways and classified ability with areas under the curve over 0.7 in receiver operating characteristic analysis, suggesting a certain accuracy for being the potential biological markers. Especially, we found that the proteins in glycerophospholipid metabolism were predicted to interact with ClC-7 and further verified that the expression of coding genes were significantly up-regulated in myeloid cell specific <italic>Clcn7<sup>G763R</sup></italic> mutant mouse.</p></sec><sec><title>Conclusion</title><p>This study provides data on serum metabolomics in osteopetrosis caused by <italic>CLCN7</italic> mutation and provides new potential metabolic markers and pathways for diagnosis and pathogenesis of osteopetrosis.</p></sec>