Despite osteoarthritis (OA) being recognised for over a century as a debilitating disease that affects millions, there are huge gaps in our understanding of the underlying pathophysiology that drives this disease. Present day studies that focussed on ubiquitination (Ub) and ubiquitylation-like (Ubl) modification related mechanisms have brought light into the possibility of attenuating OA development by targeting these specific proteins in chondrocytes. In the present review, we discuss recent advances in studies involving Ub ligases and deubiquitinating enzymes (DUBs) which are of importance in the development of OA, and may offer potential therapeutic strategies for OA. Such targets may involve attenuating proteases such as MMP1, 8, 13, 4 and several ADAMTS that are well known for their role in cartilage breakdown. Ligases such as E2 and E3 that are involved in extracellular matrix (ECM) degradation in OA and of their pathogenesis would be discussed. In addition to catabolic and degenerative downstream effects of Ub and DUBs in OA, inflammatory mechanisms most notably involving NF-κB signalling pathways regulated through Ub and using various targeting molecules would also be highlighted. Challenges, gaps and insights from clinical trials will provide valuable guidance for future investigations on targeting UPS as a therapeutic option for OA.
Keywords: Cartilage degeneration; deubiquitination; ligases; proteostasis; therapeutics; ubiquitin.
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