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However, the long-term safety of the KD and the underlying mechanism by which it delays OA remain unclear. We found that while long-term KD could ameliorate OA, it induced severe hepatic steatosis in mice. Consequently, we developed 2 versions of ketogenic-based diets: KD supplemented with vitamin D and intermittent KD. Both KD supplemented with vitamin D and intermittent KD effectively alleviated OA by significantly reducing the levels of inflammatory cytokines, cartilage loss, sensory nerve sprouting, and knee hyperalgesia without inducing hepatic steatosis. Furthermore, \u03b2-hydroxybutyrate (\u03b2-HB), a convenient energy carrier produced by adipocytes, could ameliorate OA without causing liver lesions. Mechanistically, \u03b2-HB enhanced chondrocyte autophagy and reduced apoptosis through the activation of Erb-B2 receptor tyrosine kinase 3 (ERBB3) signaling pathway; a pathway which was down-regulated in the articular chondrocytes from both OA patients and mice. Collectively, our findings highlighted the potential therapeutic value of \u03b2-HB and KD supplemented with vitamin D and intermittent KD approaches for managing OA.<\/jats:p>","DOI":"10.1093\/jbmr\/zjae176","type":"journal-article","created":{"date-parts":[[2024,11,5]],"date-time":"2024-11-05T09:25:21Z","timestamp":1730798721000},"page":"140-153","source":"Crossref","is-referenced-by-count":8,"title":["\u03b2-Hydroxybutyrate ameliorates osteoarthritis through activation of the ERBB3 signaling pathway in mice"],"prefix":"10.1093","volume":"40","author":[{"given":"Zhiqing","family":"Cai","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases , Department of Cell Biology, School of Basic Medical Sciences, , Guangzhou 510515,","place":["China"]},{"name":"Southern Medical University , Department of Cell Biology, School of Basic Medical Sciences, , Guangzhou 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Orthopedic Hospital of Guangdong Province, The Third School of Clinical Medicine, Southern Medical University, The Third Affiliated Hospital of Southern Medical University, Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongling","family":"Hu","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases , Department of Cell Biology, School of Basic Medical Sciences, , Guangzhou 510515,","place":["China"]},{"name":"Southern Medical University , Department of Cell Biology, School of Basic Medical Sciences, , Guangzhou 510515,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinghu","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Spine Surgery , Tongling People's Hospital, Tongling, 244000, Anhui,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9631-4781","authenticated-orcid":false,"given":"Xiaochun","family":"Bai","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases , Department of Cell Biology, School of Basic Medical Sciences, , Guangzhou 510515,","place":["China"]},{"name":"Southern Medical University , Department of Cell Biology, School of Basic Medical Sciences, , Guangzhou 510515,","place":["China"]},{"name":"Academy of Orthopedics , Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong Province 510630,","place":["China"]},{"name":"Department of Joint Surgery , Center for Orthopedic Surgery, Orthopedic Hospital of Guangdong Province, The Third School of Clinical Medicine, Southern Medical University, The Third Affiliated 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