ACLT is not recommended in the mouse due to the high surgical proficiency required and the development of severe OA that may involve subchondral bone erosion. The severity and location of lesions following DMM are consistent with lesions observed in aged spontaneous mouse models of OA. The DMM model has sufficient sensitivity to show disease modification, as observed with the ADAMTS-5 knock out (KO) mouse. The DMM model should be a first choice to challenge mice with gene deletions of potential targets in OA.

The semi-quantitative scoring system recommended here is simple to apply and required no specialized equipment. Scoring of the tibial plateaus was highly reproducible and more consistent than that of the femur due to the much thinner femoral cartilage. This scoring system may be a useful tool for both new and experienced scorers to sensitively evaluate models and OA mechanisms, and also provide a common paradigm for comparative evaluation across the many groups performing these analyses.

Human osteoarthritis is a progressive disease of the joints characterized by degradation of articular cartilage. Although disease initiation may be multifactorial, the cartilage destruction appears to be a result of uncontrolled proteolytic extracellular matrix destruction. A major component of the cartilage extracellular matrix is aggrecan, a proteoglycan that imparts compressive resistance to the tissue. Aggrecan is cleaved at a specific 'aggrecanase' site in human osteoarthritic cartilage; this cleavage can be performed by several members of ADAMTS family of metalloproteases. The relative contribution of individual ADAMTS proteases to cartilage destruction during osteoarthritis has not been resolved. Here we describe experiments with a genetically modified mouse in which the catalytic domain of ADAMTS5 (aggrecanase-2) was deleted. After surgically induced joint instability, there was significant reduction in the severity of cartilage destruction in the ADAMTS5 knockout mice compared with wild-type mice. This is the first report of a single gene deletion capable of abrogating the course of cartilage destruction in an animal model of osteoarthritis. These results demonstrate that ADAMTS5 is the primary 'aggrecanase' responsible for aggrecan degradation in a murine model of osteoarthritis, and suggest rational strategies for therapeutic intervention in osteoarthritis.

The scoring paradigm described here has been found to be sufficiently sensitive to discriminate between treatments and to have high reproducibility. Therefore we recommend its use for evaluation of different rat OA models as well as assessment of disease-modifying effects of treatments in these models.

Sex hormones play a critical role in the progression of OA in the murine DMM surgical model, with males having more severe OA than females. Intact females had more OA than OVX females, indicating that ovarian hormones decrease the severity of OA in the female mice. Male hormones, such as testosterone, exacerbate OA in male mice as demonstrated by the fact that ORX mice experienced less OA than intact males, and that addition of DHT to ORX males was able to counteract the effect of castration and re-establish severe OA.