Abstract
BackgroundChemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1 (MCP-1), belongs to the CC chemokine family that is associated with the disease status and outcomes of osteoarthritis (OA). Here, we investigated the intracellular signaling pathways involved in CCL2-induced vascular cell adhesion molecule-1 (VCAM-1) expression in human OA synovial fibroblasts (OASFs).Methodology/Principal FindingsStimulation of OASFs with CCL2 induced VCAM-1 expression. CCL2-mediated VCAM-1 expression was attenuated by CCR2 inhibitor (RS102895), PKCδ inhibitor (rottlerin), p38MAPK inhibitor (SB203580), and AP-1 inhibitors (curcumin and tanshinone IIA). Stimulation of cells with CCL2 increased PKCδ and p38MAPK activation. Treatment of OASFs with CCL2 also increased the c-Jun phosphorylation and c-Jun binding to the AP-1 element on the VCAM-1 promoter. Moreover, CCL2-mediated CCR2, PKCδ, p38MAPK, and AP-1 pathway promoted the adhesion of monocytes to the OASFs monolayer.Conclusions/SignificanceOur results suggest that CCL2 increases VCAM-1 expression in human OASFs via the CCR2, PKCδ, p38MAPK, c-Jun, and AP-1 signaling pathway. The CCL2-induced VCAM-1 expression promoted monocytes adhesion to human OASFs.
Highlights
Osteoarthritis (OA) is a chronic joint disorder characterized by slow progressive degeneration of articular cartilage, subchondral bone alteration, and variable secondary synovial inflammation
Conclusions/Significance: Our results suggest that CCL2 increases vascular cell adhesion molecule-1 (VCAM-1) expression in human OA synovial fibroblasts (OASFs) via the CCR2, protein kinase Cd (PKCd), p38MAPK, c-Jun, and AP-1 signaling pathway
CCL2 stimulation did not increase the binding activity of c-Jun to the VCAM-1 promoter without AP-1 binding site (Fig. 6B). These results indicate that CCL2-induced VCAM-1 expression was mediated through the CCR2, PKCd, p38MAPK, and AP-1 pathway in human OASFs
Summary
Osteoarthritis (OA) is a chronic joint disorder characterized by slow progressive degeneration of articular cartilage, subchondral bone alteration, and variable secondary synovial inflammation. The pathogenesis of the disease remains elusive, there is increasing evidence indicating that mononuclear cells migration plays an important role in the perpetuation of inflammation in synovium [3,4]. Adhesion and infiltration of mononuclear cells to inflammatory sites are regulated by adhesion molecules, such as vascular adhesion molecule-1 (VCAM-1) [5,6]. Up-regulation of VCAM-1 has been shown in the synovial lining of OA patients by immunohistochemical staining and in cultured human OASFs by Western blotting [7,8]. We investigated the intracellular signaling pathways involved in CCL2-induced vascular cell adhesion molecule-1 (VCAM-1) expression in human OA synovial fibroblasts (OASFs)
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