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At one such locus, genetic, bioinformatic, and zebrafish knockout data strongly prioritize membrane palmitoylated protein 7 (MPP7) as a candidate gene, although its precise role in bone biology remains poorly defined. MPP7 encodes a member of the p55 Stardust family of membrane-associated guanylate kinase proteins, which are key regulators of epithelial cell polarity and junctional organization. Here, we investigated the functional role of MPP7 in bone biology. We found that MPP7 expression was significantly reduced\u2014by approximately twofold\u2014in bone tissue from osteoporotic patients compared with osteoarthritic patients and non-osteoporotic controls. Furthermore, we generated a CRISPR\/Cas9-mediated MPP7 knockout in the human osteosarcoma HOS cell line and demonstrated that MPP7 deletion impairs osteogenic differentiation and completely abrogates mineralization through downregulation of ALPL expression. Knockout cells also displayed altered morphology, suggesting that MPP7 influences osteoblast function via effects on cell polarity and adhesion. Collectively, our findings, together with zebrafish genetic evidence, indicate that MPP7 plays a critical role in osteoblast differentiation and mineralization and may contribute to osteoporosis susceptibility in humans.<\/jats:p>","DOI":"10.1007\/s00223-025-01439-w","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T04:13:01Z","timestamp":1760674381000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Membrane Palmitoylated Protein 7 is Required for Osteogenesis and is Linked with Bone Mineralization and Osteoporosis: The Functional Evaluation of GEFOS GWAS Hit"],"prefix":"10.1007","volume":"116","author":[{"given":"Petra","family":"Malava\u0161i\u010d","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jasna","family":"Lojk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marija Nika","family":"Lov\u0161in","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Radko","family":"Komadina","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregor","family":"Haring","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rihard","family":"Treb\u0161e","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernando","family":"Rivadeneira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Karasik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Ostanek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6013-9758","authenticated-orcid":false,"given":"Janja","family":"Marc","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,10,17]]},"reference":[{"key":"1439_CR1","unstructured":"NIH Consens Statement (2000) Osteoporosis prevention, diagnosis, and therapy. 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Osteoarthritis Cartilage 28(4):438\u2013445","journal-title":"Osteoarthritis Cartilage"}],"container-title":["Calcified Tissue International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00223-025-01439-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00223-025-01439-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00223-025-01439-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T13:22:06Z","timestamp":1766755326000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00223-025-01439-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,17]]},"references-count":49,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["1439"],"URL":"https:\/\/doi.org\/10.1007\/s00223-025-01439-w","relation":{},"ISSN":["1432-0827"],"issn-type":[{"type":"electronic","value":"1432-0827"}],"subject":[],"published":{"date-parts":[[2025,10,17]]},"assertion":[{"value":"14 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 September 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 October 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Petra Malava\u0161ic, Jasna Lojk, Marija Nika Lov\u0161in, Radko Komadina, Gregor Haring, Rihard Treb\u0161e, Fernando Rivadeneira, David Karasik, Barbara Ostanek and Janja Marc declare no conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Bone and muscle tissue samples were obtained with informed consent. The study was approved by the Republic of Slovenia National Medical Ethics Committee (Reference Numbers: 0120\u2013523\/2016\u20132, KME 45\/10\/16).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval Statement"}},{"value":"All participants provided written informed consent in accordance with the Declaration of Helsinki.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Patient Consent Statement"}},{"value":"Not applicable. All figures and content are original.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Permission to Reproduce Material from Other Sources"}},{"value":"Not applicable.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Clinical Trial Registration"}},{"value":"All procedures involving human participants were conducted in accordance with the ethical standards of the Republic of Slovenia National Medical Ethics Committee (Reference Numbers: 0120-523\/2016-2, KME 45\/10\/16) and with the 1964 Helsinki Declaration and its later amendments. This study did not involve any animal experiments. Written informed consent was obtained from all participants prior to sample collection and participation in the study.","order":7,"name":"Ethics","group":{"name":"EthicsHeading","label":"Human and Animal Rights and Informed Consent Statements"}}],"article-number":"128"}}