期刊
DEVELOPMENTAL DYNAMICS
卷 236, 期 6, 页码 1683-1693出版社
WILEY-LISS
DOI: 10.1002/dvdy.21159
关键词
matrix metalloproteinase; type I collagen; osteopenia
资金
- NCI NIH HHS [CA094168, R01 CA094168-05, R01 CA094168, P50 CA058207, R01 CA098075, CA098075, P50 CA058207-11, P01 CA072006, P01 CA072006-10] Funding Source: Medline
- NCRR NIH HHS [U54 RR020843, U54 RR020843-04S1] Funding Source: Medline
- NIAMS NIH HHS [R01 AR046238, R01 AR046238-08] Funding Source: Medline
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 (Colla1(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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据