β-Hydroxybutyrate ameliorates osteoarthritis through activation of the ERBB3 signaling pathway in mice

作者：Zhiqing Cai, Zhimin Zhang, Jiarong Leng, Meng-Yun Xie, K. Zhang, Jingyi Zhang, Haiyan Zhang, Hongling Hu, Yinghu Deng, Xiaochun Bai, Qiancheng Song, Pinglin Lai · 发表于：Journal of Bone and Mineral Research · 年份：2024 · DOI：10.1093/jbmr/zjae176 · 被引用次数：6 · 研究领域：Diet and metabolism studies、Adipose Tissue and Metabolism、Metabolomics and Mass Spectrometry Studies

The ketogenic diet (KD) has demonstrated efficacy in ameliorating inflammation in rats with osteoarthritis (OA). 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, β-hydroxybutyrate (β-HB), a convenient energy carrier produced by adipocytes, could ameliorate OA without causing liver lesions. Mechanistically, β-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 β-HB and KD supplemented with vitamin D and intermittent KD approaches for managing OA.