Progressive cartilage degradation is considered a hallmark of osteoarthritis (OA), and as such, methods to inhibit this process have been extensively investigated as potential disease-modifying therapies. However, all tissues of the joint are affected by disease in OA, and it is likely that the pain and disability which are the major clinical symptoms of OA, arrise predominantly from pathology in these extra-cartilaginous structures. It is unclear therefore, whether specifically targeting inhibition of cartilage matrix breakdown will ameliorate global joint pathology and thereby affect the clinically-relevant OA-related disability. We have investigated this question by reviewing the literature and data available from studies of genetically-modified (GM) mice. A total of 79 different GM strains were identified in which OA-like cartilage erosion was analysed, 53 with increased, 18 with no change, and 8 with decreased cartilage damage. Inhibition of OA cartilage damage was afforded by mutations that either reduced chondrocyte hypertrophy or abrogated proteolysis of aggrecan and collagen II in cartilage. There was an association between increased cartilage breakdown and changes in subchondral bone, osteophytosis and synovial hyperplasia in GM mice. However, the effect of significantly inhibiting cartilage damage on pathology in other joints tissues has been less well examined. There appeared to be no diminution of osteophyte development in chondroprotected GM mice strains, but a possible reduction in subchondral bone plate changes. To date, there is no conclusive data on the effect of inhibiting cartilage breakdown on clinical signs of OA in GM mice. These studies have highlighted the tremendous advances studies of GM mice have afforded us in understanding the pathophysiology of cartilage degradation in OA. Furthermore they demonstrate the feasibility of targeting cartilage matrix destruction. However, it is evident that an important direction for ongoing research will be to determine the effect of successful protection of cartilage structural integrity on pathology in other tissues in the OA joint, and the clinical signs of the disease.