Journal
MECHANISMS OF AGEING AND DEVELOPMENT
Volume 205, Issue -, Pages -Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mad.2022.111688
Keywords
Osteoarthritis; Chondrocyte senescence; Fatty acid oxidation; CPT1A; Mitochondria; Mitophagy
Categories
Funding
- National Natural Sci-ence Foundation of China [81772384, 81902242]
- Guangdong Basic and Applied Basic Research Foundation [2021A1515010531, 2021A1515010621]
- Medical Science and Technology Planning Project of Zhuhai, China
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The study found that inhibiting Cpt1a can alleviate chondrocyte senescence and osteoarthritis, promoting mitochondrial function and providing a new therapeutic strategy.
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.
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