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This study has identified chaperone\u2010mediated autophagy (CMA) as a critical regulator that safeguards bone formation from the detrimental effects of excessive inflammation. By silencing LAMP2A or HSCA8, we observed a hindrance in the osteoblast differentiation of human bone marrow mesenchymal stem cells (hBMSCs) in\u00a0vitro. To further elucidate the role of LAMP2A, we generated LAMP2A gene knockdown and overexpression of mouse BMSCs (mBMSCs) using adenovirus. Our results showed that LAMP2A knockdown led to a decrease in osteogenic\u2010specific proteins, while LAMP2A overexpression favored the osteogenesis of mBMSCs. Notably, active\u2010\u03b2\u2010catenin levels were upregulated by LAMP2A overexpression. Furthermore, we found that LAMP2A overexpression effectively protected the osteogenesis of mBMSCs from TNF\u2010\u03b1, through the PI3K\/AKT\/GSK3\u03b2\/\u03b2\u2010catenin pathway. Additionally, LAMP2A overexpression significantly inhibited osteoclast hyperactivity induced by TNF\u2010\u03b1. Finally, in a murine bone defect model, we demonstrated that controlled release of LAMP2A overexpression adenovirus by alginate sodium capsule efficiently protected bone healing from inflammation, as confirmed by imaging and histological analyses. Collectively, our findings suggest that enhancing CMA has the potential to safeguard bone formation while mitigating hyperactivity in bone absorption.<\/jats:p>","DOI":"10.1096\/fj.202302425r","type":"journal-article","created":{"date-parts":[[2024,5,25]],"date-time":"2024-05-25T11:10:01Z","timestamp":1716635401000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Chaperone\u2010mediated autophagy protects the bone formation from excessive inflammation through\n                    <scp>PI3K\/AKT\/GSK3\u03b2<\/scp>\n                    \/\u03b2\u2010catenin pathway"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7766-6201","authenticated-orcid":false,"given":"Kai","family":"Hang","sequence":"first","affiliation":[{"name":"Department of Orthopaedics, the Children's Hospital Zhejiang University School of Medicine, National Clinical Research Center for Child Health  Zhejiang 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