Fang Guibin, Wen Xingzhao, Jiang Zongrui, Du Xue, Liu Ruonan, Zhang Chengyun, Huang Guiwu, Liao Weiming, Zhang Zhiqi
Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou 510080, Guangdong, China; Department of Orthopedics, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China.
Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou 510080, Guangdong, China; Department of Medicine, Solna, Karolinska Institutet, and Centre for Molecular Medicine, Karolinska University Hospital, 171 64 Stockholm, Sweden.
Mol Ther. 2023 Dec 6;31(12):3594-3612. doi: 10.1016/j.ymthe.2023.10.016. Epub 2023 Oct 14.
Osteoarthritis (OA) is the most common joint disease, but no disease-modifying drugs have been approved for OA treatment. Mitophagy participates in mitochondrial homeostasis regulation by selectively clearing dysfunctional mitochondria, which might contribute to cartilage degeneration in OA. Here, we provide evidence of impaired mitophagy in OA chondrocytes, which exacerbates chondrocyte degeneration. Among the several classic mitophagy-regulating pathways and receptors, we found that FUNDC1 plays a key role in preserving chondrocyte homeostasis by inducing mitophagy. FUNDC1 knockdown in vitro and knockout in vivo decreased mitophagy and exacerbated mitochondrial dysfunction, exacerbating chondrocyte degeneration and OA progression. FUNDC1 overexpression via intra-articular injection of adeno-associated virus alleviated cartilage degeneration in OA. Mechanistically, our study demonstrated that PFKP interacts with and dephosphorylates FUNDC1 to induce mitophagy in chondrocytes. Further analysis identified KD025 as a candidate drug for restoring chondrocyte mitophagy by increasing the FUNDC1-PFKP interaction and thus alleviating cartilage degeneration in mice with DMM-induced OA. Our study highlights the role of the FUNDC1-PFKP interaction in chondrocyte homeostasis via mitophagy induction and identifies KD025 as a promising agent for treating OA by increasing chondrocyte mitophagy.
骨关节炎（OA）是最常见的关节疾病，但尚无改善病情的药物被批准用于OA治疗。线粒体自噬通过选择性清除功能失调的线粒体参与线粒体稳态调节，这可能导致OA中的软骨退变。在此，我们提供了OA软骨细胞中线粒体自噬受损的证据，这加剧了软骨细胞退变。在几种经典的线粒体自噬调节途径和受体中，我们发现FUNDC1通过诱导线粒体自噬在维持软骨细胞稳态中起关键作用。体外敲低FUNDC1和体内敲除FUNDC1均降低了线粒体自噬并加剧了线粒体功能障碍，从而加剧了软骨细胞退变和OA进展。通过关节内注射腺相关病毒过表达FUNDC1可减轻OA中的软骨退变。从机制上讲，我们的研究表明PFKP与FUNDC1相互作用并使其去磷酸化，从而诱导软骨细胞中的线粒体自噬。进一步分析确定KD025是一种候选药物，可通过增加FUNDC1-PFKP相互作用来恢复软骨细胞的线粒体自噬，从而减轻DMM诱导的OA小鼠的软骨退变。我们的研究强调了FUNDC1-PFKP相互作用通过诱导线粒体自噬在软骨细胞稳态中的作用，并确定KD025是一种通过增加软骨细胞线粒体自噬来治疗OA的有前景的药物。
