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Inhibition of MMPs and ADAM/ADAMTS
1Division of Rheumatic Diseases, Case Western Reserve University School of Medicine, Cleveland, OH 44106, United States; Department of Medicine, Division of Rheumatic Diseases, University Hospitals Cleveland Medical Center, Foley Medical Building, 2061 Cornell Road, Room 207, Cleveland, OH 44106-5076, United States.
Abstract:
Matrix metalloproteinases (MMPs), A Disintegrin and Metalloproteinase (ADAM) and A Disintegrin and Metalloproteinase with Thrombospondin Motif (ADAMTS) are zinc-dependent endopeptidases that play a critical role in the destruction of extracellular matrix proteins and, the shedding of membrane-bound receptor molecules in various forms of arthritis and other diseases. Under normal conditions, MMP, ADAM and ADAMTS gene expression aids in the maintenance of homeostasis. However, in inflamed synovial joints characteristic of rheumatoid arthritis and osteoarthritis. MMP, ADAM and ADAMTS production is greatly increased under the influence of pro-inflammatory cytokines. Analyses based on medicinal chemistry strategies designed to directly inhibit the activity of MMPs have been largely unsuccessful when these MMP inhibitors were employed in animal models of rheumatoid arthritis and osteoarthritis. This is despite the fact that these MMP inhibitors were largely able to suppress pro-inflammatory cytokine-induced MMP production in vitro. A focus on ADAM and ADAMTS inhibitors has also been pursued. Thus, recent progress has identified the "sheddase" activity of ADAMs as a viable target and the development of GW280264X is an experimental ADAM17 inhibitor. Of note, a monoclonal antibody, GLPG1972, developed as an ADAMTS-5 inhibitor, entered a Phase I OA clinical trial. However, the failure of many of these previously developed inhibitors to move beyond the preclinical testing phase has required that novel strategies be developed that are designed to suppress both MMP, ADAM and ADAMTS production and activity.
Insights
Matrix metalloproteinases (MMPs), A Disintegrin and Metalloproteinase (ADAM), and ADAM with Thrombospondin Motif (ADAMTS) are key in arthritis. Inhibitors targeting these enzymes show limited success, necessitating novel strategies to suppress their production and activity.
Area of Science:
- Biochemistry
- Molecular Biology
- Immunology
Background:
- Matrix metalloproteinases (MMPs), A Disintegrin and Metalloproteinase (ADAM), and ADAM with Thrombospondin Motif (ADAMTS) are zinc-dependent endopeptidases crucial for extracellular matrix degradation and receptor shedding.
- In arthritis, particularly rheumatoid arthritis and osteoarthritis, pro-inflammatory cytokines significantly increase the production of MMPs, ADAMs, and ADAMTS, disrupting joint homeostasis.
- While targeting these enzymes is a therapeutic strategy, direct MMP inhibition has shown limited success in preclinical models of arthritis.
Purpose of the Study:
- To review the role of MMPs, ADAMs, and ADAMTS in arthritis pathogenesis.
- To evaluate the efficacy of current medicinal chemistry strategies targeting these enzymes.
- To highlight the need for novel therapeutic approaches that suppress both the production and activity of MMPs, ADAMs, and ADAMTS.
Main Methods:
- Literature review of studies on MMP, ADAM, and ADAMTS inhibitors in arthritis models.
- Analysis of preclinical and clinical trial data for relevant inhibitors.
- Examination of the impact of pro-inflammatory cytokines on enzyme production in vitro and in vivo.
Main Results:
- Medicinal chemistry strategies directly inhibiting MMPs have largely failed in animal models of arthritis, despite in vitro efficacy in suppressing cytokine-induced production.
- Targeting the 'sheddase' activity of ADAMs, exemplified by the experimental ADAM17 inhibitor GW280264X, is a progressing area.
- An ADAMTS-5 inhibitor (GLPG1972) has advanced to a Phase I clinical trial for osteoarthritis, though many inhibitors fail to progress beyond preclinical stages.
Conclusions:
- Direct inhibition of MMPs has proven largely ineffective in treating arthritis.
- Targeting ADAM and ADAMTS enzymes, particularly their 'sheddase' activity, represents a promising therapeutic avenue.
- Developing novel strategies to suppress both the production and activity of MMPs, ADAMs, and ADAMTS is essential for effective arthritis treatment.
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