Many studies have highlighted the importance of movement-induced mechanical stimuli in the development of functional synovial joints. However, such phenomenological results have failed to provide a full explanation of the mechanism essential for the morphogenesis of fluid-filled joint cavities. We have previously demonstrated that the large glycosaminoglycan hyaluronan (HA), in association with its principal cell surface receptor CD44, plays a major role during the morphogenesis of chick joints. We have taken cells from the surface of recently cavitated joints and subjected them to a brief period of dynamic mechanical strain (3800 microE for 10 min) and measured changes in HA synthesis/release, CD44 expression and HA synthase gene expression. In addition, we subjected cells to matrix depletion prior to the application of mechanical strain in order to examine any potential modulatory function of the ECM during the cell response to strain. Removal of the cell-associated HA-containing matrix with hyaluronidase significantly increased the release of HA into tissue culture media over 24 h and is associated with increased CD44 expression, alterations in HA synthase gene expression and enhanced binding of HA to the cell surface. Such changes in HA release were shown to be blocked by addition of exogenous HA and synergistically enhanced by the application of dynamic mechanical strain. These results show that cell-matrix interactions modify the response of embryonic cells to mechanical strain and provide further insight into the mechano-dependent mechanism of joint cavity morphogenesis.