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  2. Inhibition of Cpt1a alleviates oxidative stress-induced chondrocyte senescence via regulating mitochondrial dysfunction and activating mitophagy

Inhibition of Cpt1a alleviates oxidative stress-induced chondrocyte senescence via regulating mitochondrial dysfunction and activating mitophagy

  • Mech Ageing Dev. 2022 Jul;205:111688. doi: 10.1016/j.mad.2022.111688.
Ning Jiang 1 Baizhou Xing 2 Rong Peng 2 Jie Shang 2 Biao Wu 2 Peilun Xiao 3 Shiyuan Lin 2 Xianghe Xu 4 Huading Lu 5
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Department of Orthopedics, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong, China.
  • 4 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. Electronic address: [email protected].
  • 5 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. Electronic address: [email protected].
Abstract

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.

Keywords

CPT1A; Chondrocyte senescence; Fatty acid oxidation; Mitochondria; Mitophagy; Osteoarthritis.

Figures
Products
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  • HY-D0985A
    98.70%, Mitochondrial Membrane Potential Fluorescent Dye