%0 Journal Article
%T The roles of prostaglandin F2 in regulating the expression of matrix metalloproteinase-12 via an insulin growth factor-2-dependent mechanism in sheared chondrocytes
%J -
%D 2018
%R https://doi.org/10.1038/s41392-018-0029-2
%X 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-¦¤12,14-PGJ2 (15d-PGJ2), and PGF2¦Á, have been reported to be effective in regulating the occurrence and development of OA by activating matrix metalloproteinases (MMPs), the roles of PGF2¦Á 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 PGF2¦Á-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 PGF2¦Á, which generated synergistic effects on the expression of MMP-12 via EP2/EP3-, PGF2¦Á 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-¦ÊB)-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
%U https://www.nature.com/articles/s41392-018-0029-2