In articular cartilage, over-expression of cyclooxygenase-2 (COX-2) is a key identifying characteristic of arthritis associated with apoptotic chondrocytes. In cartilage tissue, chondrocytes are responsible for production, repair, and maintenance of the extracellular matrix (ECM) which provides mechanical support and lubrication for articular joints. We recently identified a set of protein kinases and transcription factors that activate COX-2 expression under fluid shear stress (20 dyn/cm²). In addition, key promoter binding sites of COX-2 have been determined using luciferase reporter assays, and the corresponding transcription factors for these sites (CREB, c-Jun, and C/EBP β) have been identified using electrophoretic mobility shift/supershift assays. Furthermore, cDNA microarray experiments identified a class of G-protein-coupled cell surface receptors (EP2, EP3, and EP4) for the COX-2 product, PGE₂, were upregulated after 48 hours at a fluid shear stress of 20 dyn/cm². These receptors can couple to adenylate cyclase and modulate intracellular cAMP levels leading to PKA activation, which can induce expression of pro-apoptotic genes. cDNA microarray experiments also showed that MMP-9 and MMP-13 were upregulated and TIMP-3 was downregulated at 48 hours, indicating that high levels of shear signal for the degradation of the ECM. shRNA against EP₂, EP₃, and EP₄ were constructed to determine the role of these receptors in apoptosis and in the maintenance of the ECM.