Abstract
Mechanical overloading of articular cartilage producing hydrostatic stress, tensile strain, and fluid flow results in irreversible cartilage erosion and osteoarthritis (OA). Application of high fluid shear to chondrocytes recapitulates the earmarks of OA as evidenced by the induction of proinflammatory cytokines and prostaglandins, which are capable of inducing the expression of matrix-degrading enzymes. Matrix metalloproteinase-9 (MMP-9) synthesis is detected at early but not late stages of OA. However, the underlying mechanism(s) of the MMP-9 temporal regulation remains unknown. Using the T/C-28a2 chondrocyte cell line as a model system, we demonstrated that high fluid shear induces a marked increase in MMP-9 expression at short shear exposure times (3-6 h), which falls below basal levels after prolonged shear exposure (12-48 h). High fluid shear stress induced the rapid and sustained synthesis of IL-1β, activating PI3K, ERK1/2, and JNK, which are in turn responsible for MMP-9 expression. Prolonged shear exposure (>12 h) induced 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)) synthesis, which exerted an antagonistic effect on IL-1β-mediated PI3K-, ERK1/2-, and JNK-dependent NF-κB activation, thereby suppressing MMP-9 expression in human chondrocytes. Reconstructing the signaling network that regulates shear-mediated MMP-9 expression in human chondrocytes may provide insights for developing strategies to treat arthritic disorders.