The role of TRIM proteins in chronic inflammation-associated musculoskeletal diseases

Musculoskeletal disorders (MSDs), including osteoarthritis (OA), rheumatoid arthritis (RA), osteoporosis (OP), and intervertebral disc degenerative disease (IVDD), are among the most common and serious health problems worldwide. However, despite extensive research, drug therapy for these diseases remains a major challenge. This is likely due to a poor understanding of the underlying mechanisms. Recent evidence suggests that the development of these MSDs is associated with protein dysregulation and ongoing chronic inflammation. Protein turnover is controlled by the ubiquitin-proteasome system (UPS), in which E3 ubiquitin ligases, including tripartite motif proteins (TRIMs), are responsible for substrate specificity. Since multiple TRIMs are involved in the development of MSDs, their targeting may be used to correct impaired protein turnover. The recent development of targeted protein degradation technologies has revolutionized drug discovery by selectively degrading specific proteins using the UPS. It is hypothesized that failure to resolve chronic inflammation plays a critical role in the development of MSDs, suggesting that its successful resolution will result in the alleviation of MSD-related symptoms. The process of inflammation resolution is enabled by specialized pro-resolving mediators (SPMs), which are enzymatically generated from dietary essential polyunsaturated fatty acids. Supplementation with SPMs or their stable, small-molecule receptor mimetics and agonists has shown beneficial effects in MSD animal models. In this review, we substantiate the idea that the combined use of TRIM-targeting drugs and inflammation-resolving compounds represents a promising new therapeutic approach to mitigate OA, RA, OP, and IVDD manifestations and improve patient outcomes. Methods: Aligning with the primary objectives of this review, we used a narrative-style review design to explore and critically analyze the potential links between TRIMs, chronic inflammation, and musculoskeletal disorders. Articles included in this review were identified through literature searches using PubMed (English-language original and review articles published until May 2025). The following search terms were used considering all possible combinations: "TRIM proteins", "ubiquitin proteasome system", "ubiquitin ligases", "targeted protein degradation", "proteolytic targeting chimeras", "molecular glues", "musculoskeletal disorders", "osteoarthritis", “rheumatoid arthritis", "osteoporosis", "intervertebral disc degenerative disease", "chronic inflammation", "inflammation resolution", "specialized pro-resolving mediators". Search results were supplemented by reviewing reference citations from the articles identified in the initial searches and drawing on the authors' familiarity with the published literature.