The Role Of Cyclooxygenase-2, Interleukin-1 Beta And Fibroblast Growth Factor-2 In The Activation Of Matrix Metalloproteinase-1 In Sheared-Chondrocytes And Articular Cartilage

MMP-1 expression is detected in fluid shear stress (20 dyn/cm(2))-activated and osteoarthritic human chondrocytes, however, the precise mechanisms underlying shear-induced MMP-1 synthesis remain unknown. Using primary chondrocytes and T/C-28a2 chondrocytic cells as model systems, we report that prolonged application of high fluid shear to human chondrocytes induced the synthesis of cyclooxygenase-2 (COX-2), interleukin-1 beta (IL-1 beta) and fibroblast growth factor-2 (FGF-2), which led to a marked increase in MMP-1 expression. IL-1 beta, COX-2-dependent PGE(2) activated the PI3-K/AKT and p38 signaling pathways, which were in turn responsible for MMP-1 synthesis via NF-kappa B- and c-Jun-transactivating pathways. Prolonged shear stress exposure (>12 h) induced 15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) synthesis. Although 15d-PGJ(2) suppressed PI3-K/AKT and p38 signaling pathways, it stimulated MMP-1 expression via activating heme oxygenase 1 (HO-1). The critical role of COX-2 in regulating MMP-1 expression in articular cartilage in vivo was demonstrated using COX-2(+/-) transgenic mice in the absence or presence of rofecoxib oral administration. These findings provide novel insights for developing therapeutic strategies to combat OA.