Egeblad, M., Shen, H. C. J., Behonick, D. J., Wilmes, L., Eichten, A., Korets, L. V., Kheradmand, F., Werb, Z., Coussens, L. M. (2007) Type I collagen is a genetic modifier of matrix metalloproteinase 2 in murine skeletal development. Developmental Dynamics, 236 (6). pp. 1683-1693. ISSN 10588388 (ISSN)
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 TC A and TC B fragments (Col1a1 r/r mice) have severe developmental defects resembling those observed in MMP2-null humans. Composite Mmp2 -/-;Col1a1 r/r mice were born in expected Mendelian ratios but were half the size of wild-type, Mmp2 -/-, and Col1a1 r/r mice and failed to thrive. Furthermore, composite Mmp2 -/-;Col1a1 r/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 Col1a1 r. 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. © 2007 Wiley-Liss, Inc.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Matrix metalloproteinase Osteopenia Type I collagen collagen type 1 collagenase gelatinase A article bone development bone mass calvaria cranial suture craniofacial malformation DNA modification face malformation gene interaction gene mutation human mouse nonhuman osteoclast osteolysis phenotype priority journal short stature trabecular bone wild type Animals Bone and Bones Bone Density Bone Diseases, Metabolic Collagen Type I Craniofacial Abnormalities Edema Gene Expression Regulation, Developmental Humans Joints Matrix Metalloproteinase 2 Mice Mice, Transgenic Animalia Murinae Mus |
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organism description > animal > developmental stage bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > metalloproteinases organism description > animal > mammal > rodent > mouse bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types |
| CSHL Authors: | |
| Communities: | CSHL labs > Egeblad lab |
| Depositing User: | Matt Covey |
| Date: | 2007 |
| Date Deposited: | 14 Mar 2013 19:52 |
| Last Modified: | 14 Mar 2013 19:52 |
| PMCID: | PMC2581616 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/27818 |
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