This increase in cell volume could be related to changes toa hypertrophic phenotype, associated with increased expression of hypertrophy markers (type X collagen, MMP-13) inhuman OA cartilage and in animal models of joint instability[62,63]. However, this should be viewed in the context of the volume increases occurring in hypertrophic chondrocytes in the growth plate. For example, in the rat growth plate, chondrocyte volume increases from 1000 μm3in the proliferative zone to approximately 12,000 μm3in the hypertrophiczone [23]. Although the volume change in human OA cartilage is not as dramatic, it is possible that a relatively small and focal but long-term uncompensated increase would be sufficient to stimulate the progressive development of a hypertrophic phenotype with associated changes in matrix metabolism. In any event, chondrocyte swelling arising from the reduced tissue osmolarity in OA is likely to markedly increase the risk of cell damage or death as a result of mechanical loading, since chondrocytes in swollen cartilage are highly sensitive to a single impact load. In contrast, raising mediumosmolarity, which results in cell shrinkage, is chondroprotective [64].