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  • Review Article
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Matrix metalloproteinases in arthritis: towards precision medicine

Nature Reviews Rheumatology volume 19, pages 363–377 (2023)Cite this article

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Abstract

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.

Key points

  • After activation of pro-matrix metalloproteinases (pro-MMPs) via various post-translational modifications, MMPs irreversibly digest structural proteins in joint tissues.

  • In rheumatoid arthritis, MMPs from neutrophils and pannus tissue cleave cartilage glycoproteins into remnant epitopes that enhance autoimmune processes and thereby contribute to rheumatoid arthritis pathogenesis in susceptible hosts.

  • MMPs from chondrocytes in concerted action with other metalloproteinases contribute to degenerative osteoarthritis.

  • Detection of proteoforms of MMPs from various cellular sources in blood and synovial fluids can inform the diagnosis of rheumatic diseases.

  • Clinical use of MMP inhibitors first requires firm proof of the causal effects of MMPs and knowledge about the cells and molecules involved in specific arthritis entities.

  • Development of precision diagnostics and therapeutics will be aided by the use of large data sets of analytes and patient cohorts and the integration of multi-omics data.

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Fig. 1: Timeline of MMP discoveries related to arthritis research.
Fig. 2: Comparison of major producer cell types, MMPs and TIMPs in normal, RA and OA synovium.
Fig. 3: Post-translational modifications as control of MMP activities in arthritis.

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Acknowledgements

The authors apologize to those whose relevant work could not be cited and thank their research team members for longstanding collaborations and the reviewers for constructive comments.

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Authors and Affiliations

  1. Laboratory of Immunobiology, Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium

    Bernard Grillet, Rafaela Vaz Sousa Pereira, Ahmed Abu El-Asrar & Ghislain Opdenakker

  2. Laboratory of Molecular Immunology, Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium

    Jo Van Damme, Ahmed Abu El-Asrar & Paul Proost

  3. Department of Ophthalmology, King Saud University, Riyadh, Saudi Arabia

    Ahmed Abu El-Asrar & Ghislain Opdenakker

  4. University Hospitals Gasthuisberg, UZ Leuven, KU Leuven, Leuven, Belgium

    Ghislain Opdenakker

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G.O., B.G., J.V.D. and P.P. researched data for the article. All authors made substantial contributions to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Ghislain Opdenakker.

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Nature Reviews Rheumatology thanks M. Goldring, Y. Itoh and Q.-X. Sang for their contribution to the peer review of this work.

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Glossary

Cysteine switch

Mechanism explaining the latency of matrix metalloproteinases by way of a cysteine residue in the pro-peptide; removal of the cysteine sulfhydryl from the zinc ion in the active site switches on the proteinase.

Glycoforms

Presentation of a protein with specific oligosaccharides attached, implying that any glycoprotein exists as a mixture of one protein backbone with different attached sugars.

Proteasome

Macromolecular complex with threonine proteinase activity, which cleaves misfolded intracellular proteins into short peptides that can be presented by MHC class I.

Proteoforms

Individual presentations of any protein, implying that all proteins exist as collections of variants with different post-translational modifications, such as phosphorylation, citrullination and truncations.

Remnant epitopes

Host-derived peptides after proteolytic processing by extracellular proteinases from the host or from invading microorganisms; these peptides can be altered by post-translational modifications and presented as autoantigens, mainly in MHC class II molecules.

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Grillet, B., Pereira, R.V.S., Van Damme, J. et al. Matrix metalloproteinases in arthritis: towards precision medicine. Nat Rev Rheumatol 19, 363–377 (2023). https://doi.org/10.1038/s41584-023-00966-w

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