Proteolysis Involving Matrix Metalloproteinase 13 (Collagenase-3) Is Required for Chondrocyte Differentiation That Is Associated with Matrix Mineralization

Authors

  • C. William Wu,

    1. Joint Diseases Laboratory, Shriners Hospitals for Children, Canadian Hospital and Department of Surgery, Division of Surgical Research, McGill University, Montreal, Quebec, Canada
    2. Present address: Arthritis Unit, Department of Medicine, Massachusetts General Hospital, Charlestown, Massachusetts, USA
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  • Elena V. Tchetina,

    1. Joint Diseases Laboratory, Shriners Hospitals for Children, Canadian Hospital and Department of Surgery, Division of Surgical Research, McGill University, Montreal, Quebec, Canada
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  • Fackson Mwale,

    1. Joint Diseases Laboratory, Shriners Hospitals for Children, Canadian Hospital and Department of Surgery, Division of Surgical Research, McGill University, Montreal, Quebec, Canada
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  • Karen Hasty,

    1. Department of Anatomy and Neurobiology, University of Tennessee, Memphis, Tennessee, USA
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  • Isabelle Pidoux,

    1. Joint Diseases Laboratory, Shriners Hospitals for Children, Canadian Hospital and Department of Surgery, Division of Surgical Research, McGill University, Montreal, Quebec, Canada
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  • Agnes Reiner,

    1. Joint Diseases Laboratory, Shriners Hospitals for Children, Canadian Hospital and Department of Surgery, Division of Surgical Research, McGill University, Montreal, Quebec, Canada
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  • Jeffrey Chen,

    1. Inflammatory Diseases Unit, Roche Bioscience, Palo Alto, California, USA
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  • Harold E. Van Wart,

    1. Inflammatory Diseases Unit, Roche Bioscience, Palo Alto, California, USA
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  • A. Robin Poole Ph.D., D.Sc.

    Corresponding author
    1. Joint Diseases Laboratory, Shriners Hospitals for Children, Canadian Hospital and Department of Surgery, Division of Surgical Research, McGill University, Montreal, Quebec, Canada
    • Joint Diseases Laboratory, Shriners Hospitals for Children, Canadian Hospital, 1529 Cedar Avenue, Montreal, Quebec H3G 1A6, Canada
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  • The authors have no conflict of interest.

Abstract

Collagenases are involved in cartilage matrix resorption. Using bovine fetal chondrocytes isolated from physeal cartilages and separated into a distinct prehypertrophic subpopulation, we show that in serum-free culture they elaborate an extracellular matrix and differentiate into hypertrophic chondrocytes. This is characterized by expression of type X collagen and the transcription factor Cbfa1 and increased incorporation of45Ca2+ in the extracellular matrix, which is associated with matrix calcification. Collagenase activity, attributable only to matrix metalloproteinase (MMP) 13 (collagenase-3), is up-regulated on differentiation. A nontoxic carboxylate inhibitor of MMP-13 prevents this differentiation; it suppresses expression of type X collagen, Cbfa1, and MMP-13 and inhibits increased calcium incorporation in addition to inhibiting degradation of type II collagen in the extracellular matrix. General synthesis of matrix proteins is unaffected. These results suggest that proteolysis involving MMP-13 is required for chondrocyte differentiation that occurs as part of growth plate development and which is associated with matrix mineralization.

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