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However, the mechanisms underlying the regulation of MSC adipogenic differentiation require further investigation. MGP (Matrix Gla Protein) was reported to impair the osteogenic differentiation. However, the mechanisms through which MGP regulates osteoporosis and bone-fat imbalance in MSCs are still unclear. In this study, we confirmed that the expression of MGP upregulated in osteoporosis and has a negative correlation with BMD (bone mineral density). Gain- and loss-of-function experiments were performed to ensure the role of MGP in MSC adipogenic differentiation. Mechanistically, MGP increased intracellular free Ca2+ levels and enhanced CaMKII phosphorylation, which in turn activated RIP140 protein degradation. This led to an increase in the transcription of FABP3, ultimately promoting adipogenic differentiation in MSCs. Furthermore, we demonstrated that using recombinant adeno-associated virus 9 (rAAV9) to silence MGP has the effect of alleviating bone loss and reversing the excessive bone marrow adipose tissue in mice with osteoporosis. In summary, our research has unveiled the regulatory role of MGP\/Ca2+\/CaMKII\/RIP140\/FABP3 axis in adipogenic differentiation in MSC and it might be a promising approach for osteoporosis treatment.<\/jats:p>","DOI":"10.1038\/s41420-025-02472-2","type":"journal-article","created":{"date-parts":[[2025,4,12]],"date-time":"2025-04-12T01:54:51Z","timestamp":1744422891000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["MGP regulates the adipogenic differentiation of mesenchymal stem cells in osteoporosis via the Ca2+\/CaMKII\/RIP140\/FABP3 axis"],"prefix":"10.1038","volume":"11","author":[{"given":"Xinglang","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunhui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenhao","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Quanfeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pengfei","family":"Ji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2088-9962","authenticated-orcid":false,"given":"Huatao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yibin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiahao","family":"Jin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zihao","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miao","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pei","family":"Feng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanfeng","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1837-7116","authenticated-orcid":false,"given":"Wenjie","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4317-3468","authenticated-orcid":false,"given":"Huiyong","family":"Shen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5592-6842","authenticated-orcid":false,"given":"Peng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,4,12]]},"reference":[{"key":"2472_CR1","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1016\/S0140-6736(18)32112-3","volume":"393","author":"JE Compston","year":"2019","unstructured":"Compston JE, McClung MR, Leslie WD. 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After being fully informed of the study\u2019s objectives and procedures, including the use of tissue samples, informed consent was obtained from all participants involved in the study. The animal experiments were approved by the animal ethics committee of Sun Yat-sen University, Guangzhou, China (Animal ethical approval No. SYSU-IACUC-2023-000436). We ensured that the experiments conducted complied with all recognized standards and legal requirements. And animal care follows the institutional ethics guidelines established for experiments involving animals.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"166"}}