CX3CL1 promotes MMP-3 production via the CX3CR1, c-Raf, MEK, ERK, and NF-κB signaling pathway in osteoarthritis synovial fibroblasts

Abstract

BackgroundOsteoarthritis (OA) is a degenerative joint disease that affects the cartilage, synovium, and subchondral bone and is the leading cause of disability in older populations. Specific diagnostic biomarkers are lacking; hence, treatment options for OA are limited. Synovial inflammation is very common in OA joints and has been associated with both OA’s symptoms and pathogenesis. Confirming the role of the synovium in OA pathogenesis is a promising strategy for mitigating the symptoms and progression of OA. CX3CL1 is the only member of the CX3C class of chemokines that combines the properties of chemoattractants and adhesion molecules. CX3CL1 levels in the synovium and serum were both discovered to be positively associated with OA pathogenesis. CX3CL1 and its receptor CX3CR1 belong to a family of G protein-coupled receptors. Matrix metalloproteinases (MMPs), which are responsible for matrix degradation, play a crucial role in OA progression. The relationship between CX3CL1 and MMPs in the pathophysiology of OA is still unclear.MethodsCX3CL1-induced MMP-3 production was assessed with quantitative real-time PCR and ELISA. The mechanisms of action of CX3CL1 in different signaling pathways were studied using western blot analysis, quantitative real-time PCR and ELISA. Neutralization antibodies of integrin were achieved to block the CX3CR1 signaling pathway. Luciferase assays were used to study NF-κB promoter activity.ResultsWe investigated the signaling pathway involved in CX3CL1-induced MMP-3 production in osteoarthritis synovial fibroblasts (OASFs). CX3CL1 was found to induce MMP-3 production in a concentration-dependent and time-dependent manner. Using pharmacological inhibitors and CX3CR1 small interfering RNA to block CX3CR1 revealed that the CX3CR1 receptor was involved in the CX3CL1-mediated upregulation of MMP-3. CX3CL1-mediated MMP-3 production was attenuated by c-Raf inhibitors (GW5074) and MEK/ERK inhibitors (PD98059 and U0126). The OASFs were stimulated using CX3CL1-activated p65 phosphorylation.ConclusionsOur results demonstrate that CX3CL1 activates c-Raf, MEK, ERK, and NF-κB on the MMP-3 promoter through CX3CR1, thus contributing to cartilage destruction during OA.

The Role of Inflammation in the Pathogenesis of Osteoarthritis

“…The study showed that CCL4 and CCL4L2 expressions were involved in the canonical NF-κB signaling pathway. Hou et al discovered increased expression of CX3CL1 in synovial fibroblasts from patients with osteoarthritis [9]. CX3CL1 induced MMP-3 expression in a time-dependent and dose-dependent manner by reacting with its receptor, CX3CR1 [9].…”

“…Hou et al discovered increased expression of CX3CL1 in synovial fibroblasts from patients with osteoarthritis [9]. CX3CL1 induced MMP-3 expression in a time-dependent and dose-dependent manner by reacting with its receptor, CX3CR1 [9]. Furthermore, Alaaeddine et al showed enhanced expression of CCL20 and its receptor, CCR6, in cartilages compared to controls.…”

“…MMP-3, also known as stromelysin-1, cleaves type II collagen and aggrecan. Hou et al showed that chemokine CX3CL1 induces MMP-3 production in a concentration-dependent and timedependent manner using synovial fibroblasts from patients with osteoarthritis (OASFs) [9]. Other than that, several studies showed increased MMP-3 in osteoarthritis [47,48,53,73,78,82,83].…”

“…Inflammatory components, such as cytokines and chemokines, are produced by chondrocytes and synoviocytes in the joints of patients with osteoarthritis. Synovial fibroblasts are also a source of proinflammatory cytokines and matrix-degrading enzymes under osteoarthritis condition [9]. Moreover, IFP has been shown to contain a significant amount of immune cells like macrophage and T cells.…”

Secretion profiles of three extracellular matrix metalloproteases in severe preeclampsia

“…It has been shown in patients with PE induced MMPs production is associated with endothelial dysfunction as a result of inadequate cell invasiveness, 3,7 as well as different inflammatory cytokines (IL-1β, TNFα), and chemokines production. 18,19 Our results indicate that the ratio of the act/proMMP isoforms in patients with severe PE is found mainly at actMMP with respect to healthy pregnant patients. This suggests that the regulatory system of MMPs is modified in the endothelial microenvironment of patients with severe PE.…”