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Mol. Cells

Published online March 10, 2023

© The Korean Society for Molecular and Cellular Biology

7α,25-Dihydroxycholesterol-Induced Oxiapoptophagic Chondrocyte Death via the Modulation of p53-Akt-mTOR Axis in Osteoarthritis Pathogenesis

Jeong-Yeon Seo1,3 , Tae-Hyeon Kim1,3 , Kyeong-Rok Kang1 , HyangI Lim1 , Moon-Chang Choi2 , Do Kyung Kim1 , Hong Sung Chun2 , Heung-Joong Kim1 , Sun-Kyoung Yu1 , and Jae-Sung Kim1,*

1The Institute of Dental Science, School of Dentistry, Chosun University, Gwangju 61452, Korea, 2Department of Biomedical Science, College of Natural Science and Public Health and Safety, Chosun University, Gwangju 61452, Korea, 3These authors contributed equally to this work.

Correspondence to : js_kim@chosun.ac.kr

Received: September 23, 2022; Revised: November 29, 2022; Accepted: December 5, 2022

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.

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 chondrocytes 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 biomarker, 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 chondrocytes death via oxiapoptophagy, which is a mixed mode of apoptosis, oxidative stress, and autophagy.

Keywords 7α,25-dihydroxycholesterol, chondrocytes, osteoarthritis, oxiapoptophagy, oxysterol

Article

On-line First

Mol. Cells

Published online March 10, 2023

Copyright © The Korean Society for Molecular and Cellular Biology.

7α,25-Dihydroxycholesterol-Induced Oxiapoptophagic Chondrocyte Death via the Modulation of p53-Akt-mTOR Axis in Osteoarthritis Pathogenesis

Jeong-Yeon Seo1,3 , Tae-Hyeon Kim1,3 , Kyeong-Rok Kang1 , HyangI Lim1 , Moon-Chang Choi2 , Do Kyung Kim1 , Hong Sung Chun2 , Heung-Joong Kim1 , Sun-Kyoung Yu1 , and Jae-Sung Kim1,*

1The Institute of Dental Science, School of Dentistry, Chosun University, Gwangju 61452, Korea, 2Department of Biomedical Science, College of Natural Science and Public Health and Safety, Chosun University, Gwangju 61452, Korea, 3These authors contributed equally to this work.

Correspondence to:js_kim@chosun.ac.kr

Received: September 23, 2022; Revised: November 29, 2022; Accepted: December 5, 2022

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.

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 chondrocytes 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 biomarker, 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 chondrocytes death via oxiapoptophagy, which is a mixed mode of apoptosis, oxidative stress, and autophagy.

Keywords: 7α,25-dihydroxycholesterol, chondrocytes, osteoarthritis, oxiapoptophagy, oxysterol

Mol. Cells
Feb 28, 2023 Vol.46 No.2, pp. 69~129
COVER PICTURE
The bulk tissue is a heterogeneous mixture of various cell types, which is depicted as a skein of intertwined threads with diverse colors each of which represents a unique cell type. Single-cell omics analysis untangles efficiently the skein according to the color by providing information of molecules at individual cells and interpretation of such information based on different cell types. The molecules that can be profiled at the individual cell by single-cell omics analysis includes DNA (bottom middle), RNA (bottom right), and protein (bottom left). This special issue reviews single-cell technologies and computational methods that have been developed for the single-cell omics analysis and how they have been applied to improve our understanding of the underlying mechanisms of biological and pathological phenomena at the single-cell level.

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