Type I collagen is a genetic modifier of matrix metalloproteinase 2 in murine skeletal development.
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. Developmental Dynamics 236:1683-1693, 2007. (c) 2007 Wiley-Liss, Inc.
Egeblad
Mikala
M
Department of Anatomy, University of California, San Francisco, San Francisco, California 94143-0452, USA. mikala.egeblad@usf.edu
Shen
H-C Jennifer
HC
Behonick
Danielle J
DJ
Wilmes
Lisa
L
Eichten
Alexandra
A
Korets
Lidiya V
LV
Kheradmand
Farrah
F
Werb
Zena
Z
Coussens
Lisa M
LM
D000818:Animals; D015519:Bone Density; D001851:Bone Diseases, Metabolic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001842:Bone and Bones / Q000378:metabolism*; D024042:Collagen Type I / Q000378:metabolism*; D019465:Craniofacial Abnormalities; D004487:Edema / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007596:Joints / Q000002:abnormalities / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic
D024042:Collagen Type I; D020778:Matrix Metalloproteinase 2