Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China; Institute of Regenerative Medicine and Orthopedics, Institutes of Health Central Plain, Xinxiang Medical University, Xinxiang, Henan 453003, PR China; The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453003, PR China.
Department of Physiology and Pathophysiology School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China.
Int Immunopharmacol. 2023 Feb;115:109692. doi: 10.1016/j.intimp.2023.109692. Epub 2023 Jan 9.
Although a growing body of studies recently demonstrated that circadian clock gene Bmal1 plays an important role in cartilage development and homeostasis, evidence regarding the contribution of Bmal1 in articular cartilage of OA progression is still unclear. In the present study, we investigated the direct role of Bmal1 in articular cartilage homeostasis during OA progression using tamoxifen-induced cartilage-specific knockout mice. We found that the expression of BMAL1 was decreased in OA-damaged and aging cartilage tissues. Cartilage-specific deletion of Bmal1 promoted cartilage degradation and chondrocyte apoptosis, and inhibited chondrocyte anabolism in OA mice, leading to acceleration of articular cartilage degeneration and osteophyte formation during OA progression. Mechanistic study indicated that loss of Bmal1 resulted in hyperactivation of mammalian target of rapamycin complex 1(mTORC1) signaling in OA cartilage, and pharmacological inhibition of mTORC1 signaling pathway by rapamycin alleviated partially Bmal1 ablation-induced cartilage degradation and chondrocyte apoptosis in ex vivo OA model. Therefore, our results provide the evidence of a vital role for Bmal1 in cartilage degradation in post-traumatic OA by partially regulating the mTORC1 signaling.
尽管最近越来越多的研究表明，生物钟基因 Bmal1 在软骨发育和稳态中发挥重要作用，但关于 Bmal1 在 OA 进展中关节软骨的作用的证据仍不清楚。在本研究中，我们使用他莫昔芬诱导的软骨特异性敲除小鼠研究了 Bmal1 在 OA 进展过程中对关节软骨稳态的直接作用。我们发现，BMAL1 的表达在 OA 损伤和老化的软骨组织中降低。Bmal1 在软骨中的特异性缺失促进了软骨降解和软骨细胞凋亡，并抑制了 OA 小鼠软骨细胞的合成代谢，导致在 OA 进展过程中加速了关节软骨退化和骨赘形成。机制研究表明，Bmal1 的缺失导致 OA 软骨中雷帕霉素靶蛋白复合物 1(mTORC1)信号通路的过度激活，雷帕霉素抑制 mTORC1 信号通路的药理学抑制部分缓解了体外 OA 模型中 Bmal1 缺失诱导的软骨降解和软骨细胞凋亡。因此，我们的结果提供了证据表明，Bmal1 通过部分调节 mTORC1 信号通路在创伤后 OA 中的软骨降解中起重要作用。
