Handling Editor: Jennifer Lippincott-Schwartz
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.
Footnotes
Competing interests
The authors declare no competing or financial interests.
Author contributions
Conceptualization: M.Y.A., T.M.H.; Methodology: M.Y.A., N.A., S.V., S.J.W., K.N., T.M.H.; Validation: N.A., S.W.; Formal analysis: T.M.H.; Investigation: M.Y.A., N.A., S.V., S.J.W., K.N.; Resources: K.N., T.M.H.; Data curation: M.Y.A., N.A.; Writing - original draft: M.Y.A.; Funding acquisition: T.M.H.
Funding
This work was supported by the National Institutes of Health (NIH)/National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01-AR067056 to T.M.H.); the National Center for Complementary and Integrative Health (R01-AT007373 to T.M.H.); and the Northeast Ohio Medical University to T.M.H.. Deposited in PMC for release after 12 months.
Supplementary information
Supplementary information available online at https://jcs.biologists.org/lookup/doi/10.1242/jcs.247353.supplemental
- Received April 7, 2020.
- Accepted October 12, 2020.
- © 2020. Published by The Company of Biologists Ltd
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