{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T21:19:42Z","timestamp":1757452782524,"version":"3.41.2"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T00:00:00Z","timestamp":1739404800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p><jats:italic>CLCN7<\/jats:italic> mutation caused abnormal osteoclasts, resulting in osteopetrosis. Depending on the type of mutation, <jats:italic>CLCN7<\/jats:italic> mutations can lead to severe or relatively benign forms of osteopetrosis. However, the serum metabolic alterations in osteopetrosis caused by <jats:italic>CLCN7<\/jats:italic> mutation are still unknown. We aimed to investigate the differences in the metabolome of osteopetrosis patients caused by <jats:italic>CLCN7<\/jats:italic> mutation versus healthy controls (HC), uncovering potential subtype diagnosis biomarkers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>19 osteopetrosis patients caused by <jats:italic>CLCN7<\/jats:italic> mutation and 19 HC were recruited for liquid chromatography\u2013tandem mass spectrometry analysis. The screened pathway was validated in the myeloid cell specific <jats:italic>Clcn7<jats:sup>G763R<\/jats:sup><\/jats:italic> mutant mouse model by quantitative real-time PCR analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Three metabolic pathways were significantly enriched, including glycerophospholipid metabolism (<jats:italic>P<\/jats:italic>=0.036948), arachidonic acid metabolism (<jats:italic>P<\/jats:italic>=0.0058585) and linoleic acid metabolism (<jats:italic>P<\/jats: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 <jats:italic>Clcn7<jats:sup>G763R<\/jats:sup><\/jats:italic> mutant mouse.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study provides data on serum metabolomics in osteopetrosis caused by <jats:italic>CLCN7<\/jats:italic> mutation and provides new potential metabolic markers and pathways for diagnosis and pathogenesis of osteopetrosis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2024.1418932","type":"journal-article","created":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T09:14:31Z","timestamp":1739438071000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Metabolomics study of osteopetrosis caused by CLCN7 mutation reveals novel pathway and potential biomarkers"],"prefix":"10.3389","volume":"15","author":[{"given":"Xi","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziyuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenzhen","family":"Fu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhe","family":"Wei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiemei","family":"Gu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhenlin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangtian","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weiwei","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,2,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra040952","article-title":"Osteopetrosis","volume":"351","author":"Tolar","year":"2004","journal-title":"N Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2023.116737","article-title":"Osteopetrosis: discovery and early history of \"Marble bone disease\"","volume":"171","author":"Whyte","year":"2023","journal-title":"Bone"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00223-008-9196-4","article-title":"Infantile Malignant, autosomal recessive osteopetrosis: the rich and the poor","volume":"84","author":"Villa","year":"2009","journal-title":"Calcif Tissue Int"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2017-01127","article-title":"Diagnosis and management of osteopetrosis: consensus guidelines from the osteopetrosis working group","volume":"102","author":"Wu","year":"2017","journal-title":"J Clin Endocrinol Metab"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1086\/368277","article-title":"Six novel missense mutations in the ldl receptor-related protein 5 (Lrp5) gene in different conditions with an increased bone density","volume":"72","author":"Van Wesenbeeck","year":"2003","journal-title":"Am J Hum Genet"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2022.116639","article-title":"Clcn7, a gene shared by autosomal recessive and autosomal dominant osteopetrosis","volume":"168","author":"Stauber","year":"2023","journal-title":"Bone"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3390\/cells11030366","article-title":"The role of the lysosomal cl(-)\/H(+) antiporter clc-7 in osteopetrosis and neurodegeneration","volume":"11","author":"Zifarelli","year":"2022","journal-title":"Cells"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2018.06.003","article-title":"Sclerosing bone dysplasias","volume":"32","author":"Boudin","year":"2018","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.071107","article-title":"A new heterozygous mutation (R714c) of the osteopetrosis gene, pleckstrin homolog domain containing family M (with run domain) member 1 (Plekhm1), impairs vesicular acidification and increases tracp secretion in osteoclasts","volume":"23","author":"Del Fattore","year":"2008","journal-title":"J Bone Miner Res"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2100","article-title":"Clcn7 and tcirg1 mutations differentially affect bone matrix mineralization in osteopetrotic individuals","volume":"29","author":"Barvencik","year":"2014","journal-title":"J Bone Miner Res"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.2003.18.8.1513","article-title":"Chloride channel 7 (Clcn7) gene mutations and autosomal dominant osteopetrosis, type ii","volume":"18","author":"Waguespack","year":"2003","journal-title":"J Bone Miner Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2006-1986","article-title":"Autosomal dominant osteopetrosis: clinical severity and natural history of 94 subjects with a chloride channel 7 gene mutation","volume":"92","author":"Waguespack","year":"2007","journal-title":"J Clin Endocrinol Metab"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.819641","article-title":"Natural history of type ii autosomal dominant osteopetrosis: A single center retrospective study","volume":"13","author":"Wang","year":"2022","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.130","article-title":"Elevated serum lactate dehydrogenase isoenzymes and aspartate transaminase distinguish albers-sch\u00f6nberg disease (Chloride channel 7 deficiency osteopetrosis) among the sclerosing bone disorders","volume":"25","author":"Whyte","year":"2010","journal-title":"J Bone Miner Res"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3969\/j.issn.1674-2591.2023.05.001","article-title":"Expert consensus on clinical diagnosis and treatment of osteopetrosis","volume":"16","year":"2023","journal-title":"Chin J Osteoporosis Bone Mineral Res"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3760\/cma.j.cn311282-20211224-00813","article-title":"Generation and phenotype of myeloid cell specific clcn7-mutation osteopetrosis mouse model","volume":"38","author":"Ziyuan","year":"2022","journal-title":"Chin J Endocrinol Metab"},{"key":"B17","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.plipres.2014.01.002","article-title":"Application of stable isotopes to investigate the metabolism of fatty acids, glycerophospholipid and sphingolipid species","volume":"54","author":"Ecker","year":"2014","journal-title":"Prog Lipid Res"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-021-02595-4","article-title":"Circadian regulation and clock-controlled mechanisms of glycerophospholipid metabolism from neuronal cells and tissues to fibroblasts","volume":"59","author":"Guido","year":"2022","journal-title":"Mol Neurobiol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.829425","article-title":"Comprehensive metabolic profiling of inflammation indicated key roles of glycerophospholipid and arginine metabolism in coronary artery disease","volume":"13","author":"Zhu","year":"2022","journal-title":"Front Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.620543","article-title":"Non-neuronal role of acetylcholinesterase in bone development and degeneration","volume":"8","author":"Luo","year":"2020","journal-title":"Front Cell Dev Biol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2015.05.012","article-title":"Altered ultrastructure, density and cathepsin K expression in bone of female muscarinic acetylcholine receptor M3 knockout mice","volume":"29","author":"Lips","year":"2015","journal-title":"Int Immunopharmacol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3945\/jn.116.243006","article-title":"Dietary choline intake is directly associated with bone mineral density in the hordaland health study","volume":"147","author":"\u00d8yen","year":"2017","journal-title":"J Nutr"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1007\/s00774-011-0319-z","article-title":"The virulence gene and clinical phenotypes of osteopetrosis in the chinese population: six novel mutations of the clcn7 gene in twelve osteopetrosis families","volume":"30","author":"Wang","year":"2012","journal-title":"J Bone Miner Metab"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.2003.18.10.1740","article-title":"Chloride channel clcn7 mutations are responsible for severe recessive, dominant, and intermediate osteopetrosis","volume":"18","author":"Frattini","year":"2003","journal-title":"J Bone Miner Res"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1021\/cr1004106","article-title":"Regulation and functions of diacylglycerol kinases","volume":"111","author":"Shulga","year":"2011","journal-title":"Chem Rev"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2533","article-title":"Diacylglycerol kinase Z (Dgk\u03b6) is a critical regulator of bone homeostasis via modulation of C-fos levels in osteoclasts","volume":"30","author":"Zamani","year":"2015","journal-title":"J Bone Miner Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.25461","article-title":"Dgk\u03b6 Downregulation enhances osteoclast differentiation and bone resorption activity under inflammatory conditions","volume":"232","author":"Iwazaki","year":"2017","journal-title":"J Cell Physiol"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2024.1418932\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T09:14:35Z","timestamp":1739438075000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2024.1418932\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,13]]},"references-count":27,"alternative-id":["10.3389\/fendo.2024.1418932"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2024.1418932","relation":{},"ISSN":["1664-2392"],"issn-type":[{"type":"electronic","value":"1664-2392"}],"subject":[],"published":{"date-parts":[[2025,2,13]]},"article-number":"1418932"}}