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ADAMTS and ADAM metalloproteinases in osteoarthritis - looking beyond the 'usual suspects'
C-Y Yang1, A Chanalaris1, L Troeberg1
1Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, OX3 7FY Oxford, UK.
Introduction:
Matrix metalloproteinases (MMPs) and 'aggrecanase' a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) are well established to play key roles in osteoarthritis (OA) through degradation of extracellular matrix (ECM) type II collagen and aggrecan, and are thus potential targets for development of OA therapies.
Objective:
This paper aims to provide a comprehensive review of the expression and potential roles of other, lesser-known ADAMTSs and related adamalysins (or a disintegrin and metalloproteinases (ADAMs)) in cartilage, with a view to identifying potentially protective or homeostatic metalloproteinases in the joint and informing consequent selective inhibitor design.
Design:
A comprehensive literature search was performed using PubMed terms 'osteoarthritis' and 'ADAMTS' or 'ADAM'.
Results:
Several ADAMTSs and ADAMs were identified as having reportedly increased expression in OA. These include enzymes likely to play roles in cartilage matrix anabolism (e.g., the procollagen N-proteinases ADAMTS-2, ADAMTS-3 and ADAMTS-14), chondrocyte differentiation and proliferation (e.g., ADAM9, ADAM10, ADAM12), as well as enzymes contributing to cartilage catabolism (e.g., Cartilage oligomeric protein (COMP)-degrading ADAMTS-7 and ADAMTS-12).
Conclusions:
In addition to the well-characterised MMPs, ADAMTS-4 and ADAMTS-5, many other ADAMTSs and ADAMs are expressed in cartilage and several show significantly altered expression in OA. Studies aimed at elucidating the pathophysiological roles of these enzymes in cartilage will contribute to our understanding of OA pathogenesis and enable design of targeted inhibitors that effectively target metalloproteinase-mediated cartilage degradation while sparing cartilage repair pathways.
Insights
This review explores lesser-known metalloproteinases in osteoarthritis (OA), identifying enzymes involved in cartilage repair and degradation. Understanding these matrix metalloproteinases (MMPs) and ADAMTSs is key for developing targeted OA therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Rheumatology
Background:
- Matrix metalloproteinases (MMPs) and ADAMTSs are crucial in osteoarthritis (OA) pathogenesis.
- These enzymes degrade extracellular matrix components like type II collagen and aggrecan.
- They represent potential therapeutic targets for OA treatment.
Purpose of the Study:
- To review the expression and roles of less-studied ADAMTSs and ADAMs in cartilage.
- To identify metalloproteinases that may protect or maintain homeostasis in the joint.
- To inform the design of selective inhibitors for OA therapy.
Main Methods:
- Comprehensive literature search using PubMed.
- Keywords included 'osteoarthritis', 'ADAMTS', and 'ADAM'.
- Review focused on enzymes expressed in cartilage and their altered expression in OA.
Main Results:
- Several ADAMTSs and ADAMs show increased expression in OA.
- Identified enzymes involved in cartilage anabolism (ADAMTS-2, -3, -14) and chondrocyte function (ADAM9, -10, -12).
- Cartilage-degrading enzymes like ADAMTS-7 and -12 were also noted.
Conclusions:
- Beyond MMPs, ADAMTS-4, and ADAMTS-5, numerous other ADAMTSs and ADAMs are present in cartilage.
- Many of these enzymes exhibit altered expression in OA.
- Further research into their roles will enhance understanding of OA and guide targeted inhibitor development.
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