Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that regulate lipid metabolism, glucose homeostasis, and cell proliferation, and are thought to modulate inflammation. We have previously shown that COX-2 expression, inflammation and apoptosis preferentially occur in areas of cartilage exposed to prolong periods of high laminar shear flow (20 dyn/cm², 48 hrs). Using cDNA microarray technology coupled with novel bioinformatics tools, we observed that high shear flow repressed PPARα and induced PPAR&beta/δ mRNA/protein expression and transcriptional activity. This PPAR activity modulation was eliminated in the presence of COX-2 inhibitors, thus identifying the PPAR family as likely downsteam targets of pro-inflammatory COX-2 signaling. The use of PPARα and PPARγ but not PPAR&beta/δ selective agonists reduced the shear-induced COX-2 expression and activity and increased anti-inflammatory phase 2 enzyme activity, potentially through feedback by inhibiting COX-2-dependent signaling. Alternatively, the use of shRNAs targeting PPAR&beta/&delta diminished shear-induced inflammatory signaling, and significantly increased both PPARα and PPARγ expression and activity, indicating potential cross-talk between the PPAR family members. Furthermore, PPARα or PPARγ agonists or PPAR&beta/δ knockdown significantly reduced caspase-9-dependent apoptosis in sheared chondrocytes. PPARα and PPARγ agonists therefore represent novel therapeutic tool for the treatment of inflammatory disease such as arthritis.