Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification

doi:10.1073/pnas.0407788101

Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification

^*Center for Immunology and Inflammatory Diseases, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Building 149, 13th Street, Room 8301, Boston, MA 02129; ^‡Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, Nakamachi, Koganei, Tokyo 184-8588, Japan; and ^§Departamento de Bioquimica y Biología Molecular, Instituto Universitario de Oncologia, Universidad de Oviedo, 33006 Oviedo, Spain

Communicated by Leon E. Rosenberg, Princeton University, Princeton, NJ, October 20, 2004 (received for review July 13, 2004)

Abstract

Collagenase-3 (MMP13), a member of the matrix metalloproteinase (MMP) family of neutral endopeptidases, is expressed in the skeleton during embryonic development and is highly overexpressed in human carcinomas and in chondrocytes and synovial cells in rheumatoid arthritis and osteoarthritis. To determine the functional roles of Mmp13, we generated Mmp13-null mice that showed profound defects in growth plate cartilage with markedly increased hypertrophic domains as well as delay in endochondral ossification and formation and vascularization of primary ossification centers. Absence of Mmp13 resulted in significant interstitial collagen accumulation due, in part, to the lack of appropriate collagenase-mediated cleavage that normally occurs in growth plates and primary ossification centers. Cartilaginous growth plate abnormalities persisted in adult mice and phenocopied defects observed in human hereditary chondrodysplasias. Our findings demonstrate a unique role of Mmp13 in skeletal development.

Footnotes

↵ ¶ To whom correspondence should be addressed. E-mail: krane.stephen{at}mgh.harvard.edu.
↵ † M.I. and Y.W. contributed equally to this work.
Abbreviations: dpc, days postconception; ECM, extracellular matrix; PTH, parathyroid hormone; TRAP, tartrate resistant acid phosphatase.
↵ ∥ Kennedy, A. M., Christie, P. T., Harding, B., Pannett, A. A. J., Dearlove, A., Whyte, M. P. & Thakker, R. V. (2002) J. Bone Miner. Res. 17, Suppl 1., S175 (abstr.).