Bone growth retardation in mouse embryos expressing human collagenase 1.
Cellular growth and differentiation are readouts of multiple signaling pathways from the intercellular and/or extracellular milieu. The extracellular matrix through the activation of cellular receptors transmits these signals. Therefore, extracellular matrix proteolysis could affect cell fate in a variety of biological events. However, the biological consequence of inadequate extracellular matrix degradation in vivo is not clear. We developed a mouse model expressing human collagenase (matrix metalloproteinase-1, MMP-1) under the control of Col2a1 promoter. The mice showed significant growth retardation during embryogenesis and a loss of the demarcation of zonal structure and columnar array of the cartilage. Immunological examination revealed increased degradation of type II collagen and upregulation of fibronectin and alpha(5)-integrin subunit in the transgenic cartilage. The resting zone and proliferating zone of the growth plate cartilage exhibited a simultaneous increase in bromodeoxyuridine (BrdU)-incorporated proliferating cells and terminal deoxynucleotidyl transferase-mediated X-dUTP nick-end labeling-positive apoptotic cells, respectively. Chondrocyte differentiation was not disturbed in the transgenic mice as evidenced by normal expression of the Ihh and type X collagen expression. These data demonstrate that type II collagen proteolysis is an important determinant for the skeletal outgrowth through modulation of chondrocyte survival and cartilagenous growth.
Imai
Kazushi
K
Division of Molecular Medicine, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY, USA. kimai@tky.ndu.ac.jp
Dalal
Seema S
SS
Hambor
John
J
Mitchell
Peter
P
Okada
Yasunori
Y
Horton
William C
WC
D'Armiento
Jeanine
J
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015152:Blotting, Northern; D015153:Blotting, Western; D001846:Bone Development / Q000235:genetics / Q000502:physiology*; D002356:Cartilage / Q000002:abnormalities / Q000378:metabolism; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000378:metabolism*; D005317:Fetal Growth Retardation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism; D015870:Gene Expression; D006132:Growth Plate / Q000002:abnormalities / Q000378:metabolism; D006801:Humans; D039482:Integrin alpha5 / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
C511513:COL2A1 protein, rat; C447413:Col2a1 protein, mouse; D024043:Collagen Type II; D005353:Fibronectins; D039482:Integrin alpha5; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1