We have made several new findings on the involvement of mechanical stress (mechanical stimuli) in the pathogenesis of osteoarthritis (OA). First, we found that the use of atelocollagen gels for three-dimensional culture of articular cartilage-derived cells altered gene expression and cell behavior. Mechanical stress on human articular chondrocytes in three-dimensional culture promoted gene expression of inflammatory mediators, matrix-degrading enzymes, and pain-related molecules, and gene expression of some OA-related factors was shown to be synergistically promoted by inflammatory cytokine stimulation and mechanical stress. We devised a novel method for quantifying tissue degeneration in joints, and gained insight into the relationship between tissue degeneration and gene expression and inflammatory cytokine secretion.