Journal Article

Matrix metalloproteinases in arthritis: towards precision medicine

Grillet, Bernard, Proost, Paul, Abu El-Asrar, Ahmed, Opdenakker, Ghislain, Van Damme, Jo, Pereira, Rafaela Vaz Sousa

2023

Overview

Proteolysis of structural molecules of the extracellular matrix (ECM) is an irreversible post-translational modification in all arthropathies. Common joint disorders, including osteoarthritis and rheumatoid arthritis, have been associated with increased levels of matrix remodelling enzymes, including matrix metalloproteinases (MMPs). MMPs, in concert with other host proteinases and glycanases, destroy proteoglycans, collagens and other ECM molecules. MMPs may also control joint remodelling indirectly by signalling through cell-surface receptors or by proteolysis of cytokines and receptor molecules. After synthesis as pro-forms, MMPs can be activated by various types of post-translational modifications, including proteolysis. Once activated, MMPs are controlled by general and specific tissue inhibitors of metalloproteinases (TIMPs). In rheumatoid arthritis, proteolysis of the ECM results in so-called remnant epitopes that enhance and perpetuate autoimmune processes in susceptible hosts. In osteoarthritis, the considerable production of MMP-13 by chondrocytes, often concurrent with mechanical overload, is a key event. Hence, information about the regulation, timing, localization and activities of MMPs in specific disease phases and arthritic entities will help to develop better diagnostics. Insights into beneficial and detrimental effects of MMPs on joint tissue inflammation are also necessary to plan and execute (pre)clinical studies for better therapy and precision medicine with MMP inhibitors. With the advances in proteomics and single-cell transcriptomics, two critical points need attention: neglected neutrophil MMP biology, and the analysis of net proteolytic activities as the result of balances between MMPs and their inhibitors.Matrix metalloproteinases contribute to irreversible joint remodelling in the pathogenesis of joint diseases, including rheumatoid arthritis and osteoarthritis. This article reviews several aspects of matrix metalloproteinase biology related to arthritis and discusses how they relate to opportunities for precision medicine and diagnosis.

• Publisher: Nature Publishing Group
• Subject: Cell surface / Chondrocytes / Collagen / Collagenase 3 / Epitopes / Extracellular matrix / Joint diseases / Leukocytes (neutrophilic) / Localization / Matrix metalloproteinase / Metalloproteinase / Osteoarthritis / Post-translation / Precision medicine / Proteoglycans / Proteolysis / Proteomics / Rheumatoid arthritis / Tissue inhibitor of metalloproteinases / Transcriptomics / Translation