MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover.
MT1-MMP is a membrane-bound matrix metalloproteinase (MT-MMP) capable of mediating pericellular proteolysis of extracellular matrix components. MT1-MMP is therefore thought to be an important molecular tool for cellular remodeling of the surrounding matrix. To establish the biological role of this membrane proteinase we generated MT1-MMP-deficient mice by gene targeting. MT1-MMP deficiency causes craniofacial dysmorphism, arthritis, osteopenia, dwarfism, and fibrosis of soft tissues due to ablation of a collagenolytic activity that is essential for modeling of skeletal and extraskeletal connective tissues. Our findings demonstrate the pivotal function of MT1-MMP in connective tissue metabolism, and illustrate that modeling of the soft connective tissue matrix by resident cells is essential for the development and maintenance of the hard tissues of the skeleton.
Holmbeck
K
K
MMP Unit, National Institute of Dental and Craniofacial Research, Bethesda, Maryland 20892, USA.
Bianco
P
P
Caterina
J
J
Yamada
S
S
Kromer
M
M
Kuznetsov
S A
SA
Mankani
M
M
Robey
P G
PG
Poole
A R
AR
Pidoux
I
I
Ward
J M
JM
Birkedal-Hansen
H
H
D000818:Animals; D001168:Arthritis / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D001824:Body Constitution; D001846:Bone Development; D001851:Bone Diseases, Metabolic / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D001862:Bone Resorption / Q000473:pathology; D002100:Cachexia / Q000235:genetics; D002356:Cartilage / Q000473:pathology; D003094:Collagen / Q000378:metabolism*; D003240:Connective Tissue Diseases / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D004195:Disease Models, Animal; D004392:Dwarfism / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005355:Fibrosis; D006132:Growth Plate / Q000473:pathology; D006818:Hyalin; D053511:Matrix Metalloproteinase 14; D020782:Matrix Metalloproteinases / Q000235:genetics* / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000201:enzymology / Q000473:pathology; D012867:Skin / Q000166:cytology / Q000201:enzymology; D012886:Skull / Q000473:pathology; D017154:Stromal Cells / Q000473:pathology; D013583:Synovial Membrane / Q000473:pathology
C507096:Mmp14 protein, mouse; D003094:Collagen; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D053511:Matrix Metalloproteinase 14