The roles of prostaglandin F2 in regulating the expression of matrix metalloproteinase-12 via an insulin growth factor-2-dependent mechanism in sheared chondrocytes

Osteoarthritis (OA) was recently identified as being regulated by the induction of cyclooxygenase-2 (COX-2) in response to high fluid shear stress. Although the metabolic products of COX-2, including prostaglandin (PG)E2, 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2), and PGF2α, have been reported to be effective in regulating the occurrence and development of OA by activating matrix metalloproteinases (MMPs), the roles of PGF2α in OA are largely overlooked. Thus, we showed that high fluid shear stress induced the mRNA expression of MMP-12 via cyclic (c)AMP- and PGF2α-dependent signaling pathways. Specifically, we found that high fluid shear stress (20？dyn/cm2) significantly increased the expression of MMP-12 at 6？h (？>？fivefold), which then slightly decreased until 48？h (？>？threefold). In addition, shear stress enhanced the rapid synthesis of PGE2 and PGF2α, which generated synergistic effects on the expression of MMP-12 via EP2/EP3-, PGF2α receptor (FPR)-, cAMP- and insulin growth factor-2 (IGF-2)-dependent phosphatidylinositide 3-kinase (PI3-K)/protein kinase B (AKT), c-Jun N-terminal kinase (JNK)/c-Jun, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-activating pathways. Prolonged shear stress induced the synthesis of 15d-PGJ2, which is responsible for suppressing the high levels of MMP-12 at 48？h. These in vitro observations were further validated by in vivo experiments to evaluate the mechanisms of MMP-12 upregulation during the onset of OA by high fluid shear stress. By delineating this signaling pathway, our data provide a targeted therapeutic basis for combating OA