How Proteases Regulate Bone Morphogenesis


Address for correspondence: Zena Werb, Department of Anatomy, HSW 1320/1321, University of California, 513 Parnassus Avenue, San Francisco, CA 94143-0452. Voice: 415-476-4622; fax: 415-476-4565;


Abstract: Matrix metalloproteinases (MMPs) degrade most components of the extracellular matrix (ECM), as well as many non-ECM molecules. MMPs participate in (1) degradation of ECM to allow cell migration; (2) alteration of the ECM microenvironment resulting in alteration in cellular behavior; (3) modulation of biologically active molecules by direct cleavage or release from ECM stores; (4) regulation of the activity of other proteases; and (5) cell attachment, proliferation, differentiation, and apoptosis. We have sought to understand the role of MMPs during development and tissue repair in transgenic mice. Endochondral bone formation presents a particularly interesting developmental challenge. During this process, an avascular tissue (cartilage) is converted into one of the most highly vascularized tissues (bone) in the vertebrate body. Ossification begins with invasion of the calcified hypertrophic cartilage by capillaries. Apoptosis of the terminal hypertrophic chondrocytes, degradation of the cartilage matrix, and deposition of bone matrix by osteoblasts accompanies neovascularization of the growth plate. Remodeling of ECM results in a cavity filled with vascular channels containing hematopoietic cells. Our results reveal that MMP9, MMP13, and vascular endothelial growth factor are key regulators for the remodeling of the skeletal tissues. They coordinate not only matrix degradation, but also the recruitment and differentiation of endothelial cells, osteoclasts, chondroclasts, and osteoprogenitors.