Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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7α,25-Dihydroxycholesterol-Induced Oxiapoptophagic Chondrocyte Death via the Modulation of p53-Akt-mTOR Axis in Osteoarthritis Pathogenesis

  • Jeong-Yeon Seo (The Institute of Dental Science, School of Dentistry, Chosun University) ;
  • Tae-Hyeon Kim (The Institute of Dental Science, School of Dentistry, Chosun University) ;
  • Kyeong-Rok Kang (The Institute of Dental Science, School of Dentistry, Chosun University) ;
  • HyangI Lim (The Institute of Dental Science, School of Dentistry, Chosun University) ;
  • Moon-Chang Choi (Department of Biomedical Science, College of Natural Science and Public Health and Safety, Chosun University) ;
  • Do Kyung Kim (The Institute of Dental Science, School of Dentistry, Chosun University) ;
  • Hong Sung Chun (Department of Biomedical Science, College of Natural Science and Public Health and Safety, Chosun University) ;
  • Heung-Joong Kim (The Institute of Dental Science, School of Dentistry, Chosun University) ;
  • Sun-Kyoung Yu (The Institute of Dental Science, School of Dentistry, Chosun University) ;
  • Jae-Sung Kim (The Institute of Dental Science, School of Dentistry, Chosun University)
  • Received : 2022.09.23
  • Accepted : 2022.12.05
  • Published : 2023.04.30
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Abstract

This study aimed to exploring the pathophysiological mechanism of 7α,25-dihydroxycholesterol (7α,25-DHC) in osteoarthritis (OA) pathogenesis. 7α,25-DHC accelerated the proteoglycan loss in ex vivo organ-cultured articular cartilage explant. It was mediated by the decreasing extracellular matrix major components, including aggrecan and type II collagen, and the increasing expression and activation of degenerative enzymes, including matrix metalloproteinase (MMP)-3 and -13, in chondrocytes cultured with 7α,25-DHC. Furthermore, 7α,25-DHC promoted caspase-dependent chondrocyte death via extrinsic and intrinsic pathways of apoptosis. Moreover, 7α,25-DHC upregulated the expression of inflammatory factors, including inducible nitric oxide synthase, cyclooxygenase-2, nitric oxide, and prostaglandin E2, via the production of reactive oxygen species via increase of oxidative stress in chondrocytes. In addition, 7α,25-DHC upregulated the expression of autophagy biomarkers, including beclin-1 and microtubule-associated protein 1A/1B-light chain 3 via the modulation of p53-Akt-mTOR axis in chondrocytes. The expression of CYP7B1, caspase-3, and beclin-1 was elevated in the degenerative articular cartilage of mouse knee joint with OA. Taken together, our findings suggest that 7α,25-DHC is a pathophysiological risk factor of OA pathogenesis that is mediated a chondrocyte death via oxiapoptophagy, which is a mixed mode of apoptosis, oxidative stress, and autophagy.

Keywords

Acknowledgement

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF2019R1F1A104537913).

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