Am J Physiol Cell Physiol AJP: Endocrinology and Metabolism
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Am J Physiol Cell Physiol 293: C1209-C1215, 2007. First published July 25, 2007; doi:10.1152/ajpcell.00213.2007
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EXTRACELLULAR MATRIX, CELL INTERACTIONS

Bone growth retardation in mouse embryos expressing human collagenase 1

Kazushi Imai,1 Seema S. Dalal,1 John Hambor,2 Peter Mitchell,2 Yasunori Okada,3 William C. Horton,4 and Jeanine D'Armiento1

1Division of Molecular Medicine, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York; 2Central Research Division, Pfizer Inc., Groton, Connecticut; 3Department of Pathology, School of Medicine, Keio University, Tokyo, Japan; and 4Emory Orthopaedics and Spine Center, Emory University, Atlanta, Georgia

Submitted 23 May 2007 ; accepted in final form 20 July 2007

ABSTRACT

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.

chondrocyte; fibronectin; integrin; matrix metalloproteinase; type II collagen


Address for reprint requests and other correspondence: K. Imai, Dept. of Biochemistry, Nippon Dental Univ., 1-9-20 Fujimi, Chlyoda-ku, Tokyo, Japan (e-mail: kimai{at}tky.ndu.ac.jp)






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