The ability of degradation products of the extracellular matrix (ECM) to regulate cartilage homeostasis has now been well documented. There are now numerous observations that different types of products derived from the damaged matrix can provide additional signals that can amplify catabolic processes that serve either to clear tissue components for repair or to initiate reparative signals. These fragments include fibronectin fragments (Fn-f), collagen fragments (Col-f) and hyaluronan fragments (HA-f) and likely link protein fragments (LP-f). Active fragments of other ECM components may be found in the future. ECM fragments can arise during cartilage degeneration with enhanced levels of proteinases and normal rates of matrix synthesis. Ironically and theoretically, fragments might also arise from enhanced synthesis of their native precursors but only with basal levels of proteinases and this might lead to enhanced proteinases. Further, certain types of fragments might arise from synovial tissue. The linkage between catabolic and anabolic pathways in cartilage is amply illustrated by the properties of Fn-fs in that the damage pathways initiated by Fn-fs also initiate anabolic pathways of attempted repair. Observations with Fn-fs show that lower concentrations that initiate the lowest levels of matrix metalloproteinases (MMPs) can initiate anabolic processes while higher concentrations also enhance catabolic protease driven pathways that swamp out the anabolic pathway. Anabolism might be enhanced through post-translational events such as proteolytic activation of ECM bound growth factors although other explanations are possible. Thus, fragment systems may be operative not only during damage, but also during normal metabolism and in either case, may shift metabolism in either direction, depending on the concentration of the fragments. Regulation of the fragment pathways may be through native ligands, since the ECM fragments are likely inhibitors of the native ligands and vice versa. These ECM fragment pathways may define a global pathway in which: (1) one type of fragment, such as a Fn-f, can bind either Fn or type II collage and affect not only Fn integrins but also collagen integrins and (2) one type of fragment may bind one type of integrin proximal to another type and affect integrin complexes or clusters. The signaling pathway of Fn-fs suggest that they bind to receptors and disrupt receptor clusters and this may allow internalization of receptors and initiate new pathways involving MAP kinases, Nf-kB activation and ultimately cytokine and MMP upregulation. It will be important to continue to compare the Fn-f, Col-f and HA-f pathways to determine if there is a single global mechanism that might be subject to therapeutic intervention. There are still some basic questions that need to be addressed such as whether these fragments initiate cartilage degeneration or simply amplify ongoing processes or where they are positioned in the early stages of i.e. osteoarthritis and whether or not partial vs complete inhibition of these pathways would be beneficial in a degradative state. More information of the mechanisms is needed especially far upstream at the level of membrane receptors, where re-distribution of integrins may be the key initiating event in the pathway.