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Abstract
MMP-1 expression is detected in fluid shear stress (20 dyn/cm2)-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-1β (IL-1β) and fibroblast growth factor-2 (FGF-2), which led to a marked increase in MMP-1 expression. IL-1β, COX-2-dependent PGE2 activated the PI3-K/AKT and p38 signaling pathways, which were in turn responsible for MMP-1 synthesis via NF-κB- and c-Jun-transactivating pathways. Prolonged shear stress exposure (>12 h) induced 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) synthesis. Although 15d-PGJ2 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.
Highlights
Osteoblasts via cAMP-PKA signaling pathway[4]
We demonstrate that high fluid shear stress induces the synthesis and crosstalk of COX-2, IL-1β and fibroblast growth factor-2 (FGF-2), resulting in the rapid (2 h) and transient synthesis of PGE2 that activates the PI3-K/AKT, p38-dependent NF-κ B- and c-Jun-transactivating signaling pathways, which are responsible for MMP-1 activation at 12 h
COX-2 regulates the induction of IL-1β, FGF-2 and MMP-1 in shear-activated chondrocytes
Summary
Osteoblasts via cAMP-PKA signaling pathway[4]. In addition, cyclooxygenase-2 (COX-2) inhibition by NS398 treatment diminished the effects of Chlamydia pneumoniae on the induction of PGE2 and MMP-1 synthesis[5]. 15d-PGJ2 has been reported to induce synthesis of MMP-1 through a peroxisome proliferator-activated receptor-γ (PPAR-γ )-independent pathway in human breast cancer[6] and microvascular endothelial cells[7]. We demonstrate that high fluid shear stress induces the synthesis and crosstalk of COX-2, IL-1β and FGF-2, resulting in the rapid (2 h) and transient synthesis of PGE2 that activates the PI3-K/AKT-, p38-dependent NF-κ B- and c-Jun-transactivating signaling pathways, which are responsible for MMP-1 activation at 12 h. Prolonged shear stress exposure (> 12 h) induces 15d-PGJ2 synthesis, which activates MMP-1 via heme oxygenase 1 (HO-1) in human chondrocytes. These in vitro findings were further substantiated by in vivo data, thereby establishing the key roles of COX-2-derived products, IL-1β and FGF-2 in MMP-1 induction
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