Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification.
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.
Inada
Masaki
M
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, USA.
Wang
Yingmin
Y
Byrne
Michael H
MH
Rahman
Mahboob U
MU
Miyaura
Chisato
C
López-Otín
Carlos
C
Krane
Stephen M
SM
D000818:Animals; D002356:Cartilage / Q000002:abnormalities / Q000201:enzymology* / Q000254:growth & development*; D017364:Collagenases / Q000235:genetics / Q000502:physiology*; D004622:Embryo, Mammalian; D005097:Exostoses, Multiple Hereditary / Q000235:genetics; D005121:Extremities; D006132:Growth Plate / Q000254:growth & development*; D006651:Histocytochemistry; D053509:Matrix Metalloproteinase 13; D051379:Mice; D018345:Mice, Knockout; D009999:Ossification, Heterotopic; D010641:Phenotype
D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse