Mitochondrial dysfunction triggers a catabolic response in chondrocytes via ROS-mediated activation of the JNK/AP1 pathway.

Abstract

Mitochondrial function is impaired in osteoarthritis (OA) but its impact on cartilage catabolism is not fully understood. Here, we investigated the molecular mechanism of mitochondrial dysfunction-induced activation of the catabolic response in chondrocytes. Using cartilage slices from normal and OA cartilage, we showed that mitochondrial membrane potential was lower in OA cartilage, and that this was associated with increased production of mitochondrial superoxide and catabolic genes [interleukin 6 (IL-6), COX-2 (also known as PTGS2), MMP-3, -9, -13 and ADAMTS5]. Pharmacological induction of mitochondrial dysfunction in chondrocytes and cartilage explants using carbonyl cyanide 3-chlorophenylhydrazone increased mitochondrial superoxide production and the expression of IL-6, COX-2, MMP-3, -9, -13 and ADAMTS5, and cartilage matrix degradation. Mitochondrial dysfunction-induced expression of catabolic genes was dependent on the JNK (herein referring to the JNK family)/activator protein 1 (AP1) pathway but not the NFκB pathway. Scavenging of mitochondrial superoxide with MitoTEMPO, or pharmacological inhibition of JNK or cFos and cJun, blocked the mitochondrial dysfunction-induced expression of the catabolic genes in chondrocytes. We demonstrate here that mitochondrial dysfunction contributes to OA pathogenesis via JNK/AP1-mediated expression of catabolic genes. Our data shows that AP1 could be used as a therapeutic target for OA management.This article has an associated First Person interview with the first author of the paper.

• Authors: Mohammad Y Ansari, Nashrah Ahmad, Sriharsha Voleti, Saima J Wase, Kimberly Novak, Tariq M Haqqi
• Journal: Journal of cell science (J Cell Sci) Vol. 133 Issue 22 (11 30 2020) ISSN: 1477-9137 [Electronic] England
• PMID: 33097606 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020. Published by The Company of Biologists Ltd.

Chemical References

• Interleukin-1beta
• Reactive Oxygen Species
• Transcription Factor AP-1

Topics

• Cartilage, Articular (metabolism)
• Cells, Cultured
• Chondrocytes (metabolism)
• Humans
• Interleukin-1beta (metabolism)
• MAP Kinase Signaling System
• Mitochondria
• Reactive Oxygen Species (metabolism)
• Transcription Factor AP-1 (genetics, metabolism)