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.
Highlights
Metalloproteinase-9 (MMP-9) is detected at the early but not late stages of osteoarthritis
We further demonstrate the critical roles of the extracellular signal-regulated kinase (ERK1/2), phosphatidylinositol 3-kinases (PI3K), and c-Jun NH2-terminal kinase (JNK) signaling pathways, which are downstream of IL-1 and 15d-PGJ2, in the regulation of Matrix metalloproteinase-9 (MMP-9) expression via the NF-B p65 subunit at short and long shear exposure times
matrix metalloproteinases (MMPs)-9 expression in chondrocytes has been reported to be up-regulated at the early but not the late stages of OA [11]. In view of these observations [11] and given that application of high shear stress to T/C-28a2 chondrocytes for short versus long exposure times recapitulates the earmarks of OA at early and late disease stages, respectively [3, 13,14,15], we hypothesized that MMP-9 expression is temporally regulated by fluid shear
Summary
Metalloproteinase-9 (MMP-9) is detected at the early but not late stages of osteoarthritis. Results: Application of high fluid shear to chondrocytes recapitulates the temporal regulation of MMP-9 expression. Prolonged shear exposure (>12 h) induced 15-deoxy-⌬12,14-prostaglandin J2 (15d-PGJ2) synthesis, which exerted an antagonistic effect on IL-1-mediated PI3K-, ERK1/ 2-, and JNK-dependent NF-B activation, thereby suppressing MMP-9 expression in human chondrocytes. OA is classified as a noninflammatory joint disease, the progressive erosion of cartilage involves the action of cytokines and prostaglandins (PGs), which are capable of inducing the expression of matrix-degrading enzymes such as matrix metalloproteinases (MMPs) [4]. In agreement with in vivo results [11], we demonstrate the temporal regulation of MMP-9 expression in shear-activated T/C-28a2 chondrocytes, which reaches maximal levels at short shear exposure times and declines below basal levels after prolonged shear exposure. We show that the antagonistic actions of endogenous shear-induced IL-1 and 15-deoxy-⌬12,14-prostaglandin J2 (15d-PGJ2) regulate the temporal synthesis of MMP-9 in human chondrocytes. We further demonstrate the critical roles of the extracellular signal-regulated kinase (ERK1/2), phosphatidylinositol 3-kinases (PI3K), and c-Jun NH2-terminal kinase (JNK) signaling pathways, which are downstream of IL-1 and 15d-PGJ2, in the regulation of MMP-9 expression via the NF-B p65 subunit at short and long shear exposure times
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