Osteoarthritis (OA) is a globally prevalent degenerative joint disease characterized by progressive cartilage destruction, synovial inflammation, subchondral bone remodeling and osteophyte formation. Although it is well established that genetic, environmental, biomechanical factors and chronic inflammation may be involved in the progression of OA, the precise pathogenesis of OA remains only partially understood. Protein ubiquitination is an important class of post-translational modifications that affects the stability and localization of proteins by modifying specific proteins with ubiquitination and has been found to be associated with various diseases, including cardiovascular diseases, neoplasms, nerve degeneration and OA. E3 ubiquitin ligase plays a particularly essential role in the process of ubiquitination modification with its ability to specifically recognize protein substrates. At present, E3 ubiquitin ligases from the neural precursor cell expressed developmentally down-regulated protein 4 (NEDD4) family are receiving increasing attention in research on the pathophysiology of OA. They accelerate or improve the occurrence and development of OA by using targeted ubiquitination to control the function and homeostasis of cartilage and bone cells. The review summarizes an overview of the relationship between common E3 ubiquitin ligases in the NEDD4 family and OA processes such as proliferation, differentiation, apoptosis, autoimmune activity, and inflammation and explores the potential of targeted E3 ubiquitin ligase regulation in the treatment of OA, thereby providing a new strategy for diagnosis and treatment of OA in clinical  strategies.

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