The primary goal of our research has been to quantify the in vivo loading of normal and osteoarthritic (OA) joints, and to determine the corresponding biological responses. Much of the research in this area has been performed using articular cartilage explants. We feel that, although critically important to our understanding of cartilage mechanics and biology, these experiments may not be directly transferable to interpreting the in vivo joint mechanics and elucidating the detailed mechanisms of onset and progression of OA. Therefore, we have attempted to measure the loading of the knee in freely moving feline and lapine models of OA. We have found that, upon anterior cruciate ligament transection in the cat, knee joints are more flexed, muscle forces are decreased and muscle control patterns are destroyed. Articular cartilage initially becomes thicker, softer and more permeable, resulting in generally increased joint contact areas and decreased peak pressures in the initial stages of joint degeneration compared to control values. Based on our results, we speculate that unloading of the joint (rather than overloading), combined with poor muscular control and weakness, might constitute risks for the onset of joint degeneration.