Type I collagen is a genetic modifier of matrix metalloproteinase 2 in murine skeletal development

Authors

  • Mikala Egeblad,

    Corresponding author
    1. Department of Anatomy, University of California, San Francisco, San Francisco, California
    • Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, Box 0452, San Francisco, CA 94143-0452
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  • H.-C. Jennifer Shen,

    1. The Cancer Research Institute, Department of Pathology and Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California
    Current affiliation:
    1. National Cancer Institute, Center for Cancer Research, Advanced Technology Center, Rm110, 8717 Grovemont Circle, Bethesda, MD 20892-4605
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  • Danielle J. Behonick,

    1. Department of Anatomy, University of California, San Francisco, San Francisco, California
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  • Lisa Wilmes,

    1. Department of Radiology, University of California, San Francisco, San Francisco, California
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  • Alexandra Eichten,

    1. The Cancer Research Institute, Department of Pathology and Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California
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  • Lidiya V. Korets,

    1. The Cancer Research Institute, Department of Pathology and Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California
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  • Farrah Kheradmand,

    1. Division of Pulmonary and Critical Care, Baylor College of Medicine, Houston, Texas
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  • Zena Werb,

    1. Department of Anatomy, University of California, San Francisco, San Francisco, California
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  • Lisa M. Coussens

    1. The Cancer Research Institute, Department of Pathology and Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California
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Abstract

Recessive inactivating mutations in human matrix metalloproteinase 2 (MMP2, gelatinase A) are associated with syndromes that include abnormal facial appearance, short stature, and severe bone loss. Mmp2−/− mice have only mild aspects of these abnormalities, suggesting that MMP2 function is redundant during skeletal development in the mouse. Here, we report that Mmp2−/− mice with additional mutations that render type I collagen resistant to collagenase-mediated cleavage to TCA and TCB fragments (Col1a1r/r mice) have severe developmental defects resembling those observed in MMP2-null humans. Composite Mmp2−/−;Col1a1r/r mice were born in expected Mendelian ratios but were half the size of wild-type, Mmp2−/−, and Col1a1r/r mice and failed to thrive. Furthermore, composite Mmp2−/−;Col1a1r/r animals had very abnormal craniofacial features with shorter snouts, bulging skulls, incompletely developed calvarial bones and unclosed cranial sutures. In addition, trabecular bone mass was reduced concomitant with increased numbers of bone-resorbing osteoclasts and osteopenia. In vitro, MMP2 had a unique ability among the collagenolytic MMPs to degrade mutant collagen, offering a possible explanation for the genetic interaction between Mmp2 and Col1a1r. Thus, because mutations in the type I collagen gene alter the phenotype of mice with null mutations in Mmp2, we conclude that type I collagen is an important modifier gene for Mmp2. Developmental Dynamics 236:1683–1693, 2007. © 2007 Wiley-Liss, Inc.

Ancillary