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Novel selective MMP-13 inhibitors reduce collagen degradation in bovine articular and human osteoarthritis cartilage explants

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Abstract

Objective

MMP-13 is highly upregulated in arthritis and therefore strongly implicated in the pathogenesis of osteoarthritis (OA). Selective inhibition of MMP-13 may provide the desired cartilage degradation protection, while overcoming the musculoskeletal toxicity seen with nonselective inhibition of MMPs.

Methods

Activity and selectivity of novel MMP-13 inhibitors were determined in enzymatic and collagenase assays. Inhibition kinetics and competitive binding experiments were performed. The inhibition of collagen degradation was studied in cartilage explants from OA patients and in bovine and human articular cartilage systems.

Results

We have identified a new class of very potent and highly selective non-zinc-binding MMP-13 inhibitors. Selective MMP-13 inhibitors completely blocked type II collagen degradation in bovine explants and showed up to 80% inhibition in human OA cartilage.

Conclusions

These results indicate MMP-13 as the primary collagenase in the human OA cartilage and in the IL-1/OSM-induced cartilage degradation process and suggest that selective MMP-13 inhibitors may be a potential treatment of OA.

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Acknowledgments

We thank Joshua Van Veldhuizen, Timothy Powers, and Arthur G. Taveras from Alantos Pharmaceuticals Inc., Cambridge, MA, and Jürgen Boer and Christoph Steeneck from Alantos Pharmaceuticals AG, Heidelberg, Germany, for the synthesis of the inhibitors; Wiltrud Richter and Helge Bertram from the Orthopaedic University Hospital Heidelberg, Germany, for supplying us with human OA cartilage; and A. Robin Poole, Arthur G. Taveras, and Vijay Baragi for helpful discussions.

Author information

Author notes

  1. Dorothea Piecha

    Present address: Fresenius Medical Care Deutschland GmbH, Else-Kroener-Strasse 1, 61352, Bad Homburg, Germany

  2. Jürgen Weik

    Present address: Affimed Therapeutics AG, Technologiepark, Im Neuenheimer Feld 582, 69120, Heidelberg, Germany

  3. Heike Kheil & Michael W. Hofmann

    Present address: X2-Pharma GmbH, Im Neuenheimer Feld 584, 69120, Heidelberg, Germany

  4. Gabriele Becher

    Present address: Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Str. 173, 55216, Ingelheim am Rhein, Germany

  5. Andreas Timmermann

    Present address: Bayer Healthcare AG, 42096, Elberfeld, Germany

  6. Andreas Jaworski

    Present address: Drug Metabolism and Pharmacokinetics, Bioanalytical Section F, Hoffmann-La Roche Ltd, 4070, Basel, Switzerland

Authors and Affiliations

  1. Alantos Pharmaceuticals AG, Heidelberg, Germany

    Dorothea Piecha, Jürgen Weik, Heike Kheil, Gabriele Becher, Andreas Timmermann, Andreas Jaworski, Maren Burger & Michael W. Hofmann

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  1. Dorothea Piecha
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Correspondence to Dorothea Piecha.

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Responsible Editor: J. Di Battista.

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Piecha, D., Weik, J., Kheil, H. et al. Novel selective MMP-13 inhibitors reduce collagen degradation in bovine articular and human osteoarthritis cartilage explants. Inflamm. Res. 59, 379–389 (2010). https://doi.org/10.1007/s00011-009-0112-9

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  • DOI: https://doi.org/10.1007/s00011-009-0112-9

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