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Drug Insight: aggrecanases as therapeutic targets for osteoarthritis

Abstract

In healthy cartilage, effective weight-bearing requires a high concentration of intact aggrecan. Degradation and loss of aggrecan are features of osteoarthritis (OA). It is unclear whether ADAMTS-4, ADAMTS-5, or both of these aggrecanases from the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) enzyme family, are responsible for aggrecanolysis in human OA, and at what stage of disease these enzymes are active. Several potential disease-modifying agents for OA include glucosamine and chondroitin sulfate, diacerhein, and pentosan polysulfate; although their mechanisms of action in vivo are unknown, data from in vitro studies and animal models suggest that their efficacy might be partly due to inhibition of proinflammatory pathways that lead to downregulation of ADAMTS enzymes. Some histone deacetylase inhibitors that are successfully used to treat cancer can block ADAMTS-5 expression; however, these inhibitors will only be considered as potential therapies for OA if their toxicity is markedly reduced. ADAMTS inhibitors currently in development are expected to show excellent specificity now that crystal structures for several ADAMTS enzymes are available to guide drug design. ADAMTS-4 and ADAMTS-5 are appropriate targets for OA therapies, but ultimately, inhibitors of these enzymes will form only part of a larger arsenal of therapies.

Key Points

  • Most aggrecan fragments in the synovial fluid and cartilage of patients with osteoarthritis (OA) are the products of aggrecanase cleavage

  • The possibility that both a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 and ADAMTS-5 have key roles in human OA cannot be excluded, as changes in ADAMTS expression and activity at different stages of disease remain poorly characterized

  • Studies using ADAMTS inhibitors, or inducible ADAMTS knockout strategies, are needed to determine whether inhibiting ADAMTS activity in established disease can prevent progression of cartilage erosion

  • In humans, ADAMTS-5 is constitutively expressed in chondrocytes and synoviocytes, whereas ADAMTS-4 expression is induced by proinflammatory cytokines; this differential gene regulation has implications, and complications, for therapeutic strategies aimed at inhibiting both aggrecanases

  • Glucosamine and chondroitin sulfate, pentosan polysulfate and diacerhein might indirectly inhibit ADAMTS activity, although a direct cause-and-effect relationship between effects seen in vitro or in animal models, and efficacy in clinical studies, has not been established

  • Many therapies showing promise for the management of OA inhibit components of proinflammatory pathways that lead to altered ADAMTS activity

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Figure 1: ADAMTS-meditated cleavage of aggrecan compromises cartilage function.
Figure 2: The domain structure and features of ADAMTS-4 and ADAMTS-5.
Figure 3: ADAMTS enzymes with aggrecanase activity in vitro.

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Acknowledgements

The authors are grateful to Professor Stefan Lohmander for his clinical insights and improvements to the manuscript.

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Correspondence to Amanda J Fosang.

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AJ Fosang declared grant/research support from AstraZeneca and Pfizer, Inc. CB Little declared grant/research support from Fidia Farmaceutucci, Mesoblast Inc and Pfizer, Inc.

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Fosang, A., Little, C. Drug Insight: aggrecanases as therapeutic targets for osteoarthritis. Nat Rev Rheumatol 4, 420–427 (2008). https://doi.org/10.1038/ncprheum0841

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