Cartilage homeostasis: Modulation of cells and extracelllar matrix assembly

Abstract: The cartilage extracellular matrix consists of the collagen network which enmeshes the large aggregating proteoglycan, aggrecan. Accessory molecules regulate the formation and maintenance of these structures. This thesis studies aspects of cartilage assembly during development and its degradation in disease, focusing on the collagen network. In the first paper, a model of cartilage degradation is studied. Two molecules with collagen-binding capacity, cartilage oligomeric matrix protein (COMP) and chondroadherin, are released. The early release and the degradation of these components may reflect early stages in disease and is initiated by a fragment of a molecule putatively present in the joint. It may represent initial steps in loosening of the collagen network. Chondroadherin is an integrin-binding protein, and the release observed in Paper I may lead to a change in signaling to the chondrocytes. In the second paper cell studies of responses to binding to chondroadherin demonstrated modulated intracellular signaling and altered synthesis and secretion of some proteins. During development, cartilage is laid down as a template for bone. The third paper describes a novel role for chondroitin sulphated perlecan in the organization of cartilage in development, by organizing collagen. CS-substituted perlecan is shown to facilitate collagen fibrillogenesis, as does the freed CS-chain. Perlecan substituted with heparan sulphate does not display this activity. This finding offers a mechanism for the observed skeletal defects in perlecan-null mice and a novel mechanism for catalyzing collagen fibril formation in tissue.