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

IF 5.1 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Zhiqing Cai, Zhimin Zhang, Jiarong Leng, Mengyun Xie, Kang Zhang, Jingyi Zhang, Haiyan Zhang, Hongling Hu, Yinghu Deng, Xiaochun Bai, Qiancheng Song, Pinglin Lai
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引用次数: 0

Abstract

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 two 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.

β-羟基丁酸盐通过激活小鼠的 ERBB3 信号通路改善骨关节炎。
生酮饮食(KD)在改善骨关节炎(OA)大鼠的炎症方面已被证明具有疗效。然而,生酮饮食的长期安全性及其延缓 OA 的潜在机制仍不清楚。我们发现,虽然长期 KD 可以改善 OA,但它会诱发小鼠严重的肝脏脂肪变性。因此,我们开发了两种生酮饮食:补充维生素 D 的生酮饮食和间歇性生酮饮食。补充维生素 D 的生酮饮食和间歇性生酮饮食都能有效缓解 OA,显著降低炎性细胞因子水平、软骨损失、感觉神经萌发和膝关节痛觉减退,但不会诱发肝脏脂肪变性。此外,β-羟丁酸(β-HB)是脂肪细胞产生的一种方便的能量载体,它可以在不引起肝脏病变的情况下改善 OA。从机理上讲,β-HB 可通过激活 Erb-B2 受体酪氨酸激酶 3(ERBB3)信号通路增强软骨细胞的自噬作用并减少细胞凋亡;而ERBB3 信号通路在 OA 患者和小鼠的关节软骨细胞中均被下调。总之,我们的研究结果凸显了β-HB和KD辅以维生素D以及间歇性KD治疗OA的潜在治疗价值。
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来源期刊
Journal of Bone and Mineral Research
Journal of Bone and Mineral Research 医学-内分泌学与代谢
CiteScore
11.30
自引率
6.50%
发文量
257
审稿时长
2 months
期刊介绍: The Journal of Bone and Mineral Research (JBMR) publishes highly impactful original manuscripts, reviews, and special articles on basic, translational and clinical investigations relevant to the musculoskeletal system and mineral metabolism. Specifically, the journal is interested in original research on the biology and physiology of skeletal tissues, interdisciplinary research spanning the musculoskeletal and other systems, including but not limited to immunology, hematology, energy metabolism, cancer biology, and neurology, and systems biology topics using large scale “-omics” approaches. The journal welcomes clinical research on the pathophysiology, treatment and prevention of osteoporosis and fractures, as well as sarcopenia, disorders of bone and mineral metabolism, and rare or genetically determined bone diseases.
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