Department of Orthopedics, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong, China; Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong, China; Department of Orthopedics, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, Shandong, China.
Department of Orthopedics, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong, China; Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong, China.
Mech Ageing Dev. 2022 Jul;205:111688. doi: 10.1016/j.mad.2022.111688. Epub 2022 Jun 18.
Osteoarthritis (OA) is an age-related chronic degenerative disease, and chondrocyte senescence has been established to play an important role in the pathological process. There is ample evidence to suggest that lipid metabolism plays an important role in the aging process. However, the effect of lipid metabolism on chondrocyte senescence and OA remains unclear. Accordingly, we constructed a TBHP-induced senescent chondrocytes model and a destabilization of the medial meniscus (DMM) mouse model. We found that lipid accumulation and fatty acid oxidation were enhanced in senescent chondrocytes. Interestingly, carnitine palmitoyltransferase 1A (Cpt1a), the rate-limiting enzyme for fatty acid oxidation, was highly expressed in senescent chondrocytes and murine knee cartilage tissue. Suppressing Cpt1a expression using siRNA or Etomoxir, an inhibitor of Cpt1a, could attenuate oxidative stress-induced premature senescence and OA phenotype of primary murine chondrocytes, decrease cellular ROS levels, restore mitochondrial function, and maintain mitochondrial homeostasis via activating mitophagy. In vivo, pharmacological inhibition of Cpt1a by Etomoxir attenuated cartilage destruction, relieved joint space narrowing and osteophyte formation in the DMM mouse model. Overall, these findings suggested that knockdown of Cpt1a alleviated chondrocyte senescence by regulating mitochondrial dysfunction and promoting mitophagy, providing a new therapeutic strategy and target for OA treatment.
骨关节炎（OA）是一种与年龄相关的慢性退行性疾病，已有研究证实软骨细胞衰老在其病理过程中发挥重要作用。有充分的证据表明，脂代谢在衰老过程中起着重要作用。然而，脂代谢对软骨细胞衰老和 OA 的影响尚不清楚。因此，我们构建了 TBHP 诱导的衰老软骨细胞模型和内侧半月板不稳定（DMM）小鼠模型。我们发现衰老软骨细胞中脂质积累和脂肪酸氧化增强。有趣的是，脂肪酸氧化的限速酶肉毒碱棕榈酰基转移酶 1A（Cpt1a）在衰老的软骨细胞和小鼠膝关节软骨组织中高表达。使用 siRNA 或 Cpt1a 抑制剂 Etomoxir 抑制 Cpt1a 的表达可减轻氧化应激诱导的原代小鼠软骨细胞过早衰老和 OA 表型，降低细胞 ROS 水平，恢复线粒体功能，并通过激活自噬维持线粒体稳态。在体内，用 Etomoxir 抑制 Cpt1a 的药理学作用可减轻软骨破坏，缓解 DMM 小鼠模型中的关节间隙变窄和骨赘形成。总之，这些发现表明，敲低 Cpt1a 通过调节线粒体功能障碍和促进自噬来减轻软骨细胞衰老，为 OA 的治疗提供了新的治疗策略和靶点。
