Chemerin promotes MAPK/ERK activation to induce inflammatory factor production in rat synoviocytes

Abstract

Chemerin is a chemokine found in adipose tissue that specifically binds to the G protein-coupled receptor, chemokine-like receptor 1, and acts as a chemoattractant for macrophages and dendritic cells. Chemerin levels in the synovial fluid are associated with disease severity in patients with osteoarthritis (OA). However, to the best of our knowledge, the specific mechanism through which chemerin exerts its effects in OA remains unclear. The present study aimed to investigate the underlying mechanism of chemerin-associated synoviocyte inflammation. A Cell Counting Kit-8 assay was used to determine the optimal concentration of chemerin that exerted an effect on the viability of normal rat synoviocytes. The expression levels of MEK/ERK signaling pathway-related marker genes, including MEK, ERK, MMP-3 and MMP-13, were detected using reverse transcription-quantitative PCR. In addition, chemerin-induced phosphorylation of MEK, ERK1/2 and p38 MAPK was analyzed using western blotting, and the production of inflammatory factors following chemerin treatment was determined using ELISA. For the in vivo assessment of the effect of chemerin, Sprague Dawley rats underwent knee surgery to establish an arthritis model. The knee joints were then injected with normal saline or recombinant chemerin, and the synovium and knee joint tissues were harvested for H&E histological observations after 3 weeks. In addition, synovial tissue was analyzed for the production of inflammatory factors by ELISA. The results of the present study revealed that chemerin enhanced the viability of synoviocytes in a dose-dependent manner. The stimulatory effect of chemerin on synoviocytes was shown to be accompanied by the activation of MEK, ERK1/2 and p38 MAPK, which was associated with the production of MMP-13, MMP-3, TNF-α, IL-6 and IL-1β by synoviocytes. Inhibition of the ERK1/2 signaling pathway significantly reduced chemerin-induced MMP-13, MMP-3, TNF-α, IL-6 and IL-1β production. H&E staining showed that synovial hyperplasia and articular cartilage wear were more severe in chemerin treated rats after knee surgery than in knee surgery alone and saline controls. In addition, the articular cartilage surface was damaged, and the synovial tissue showed inflammatory cell infiltration. In Sprague Dawley rats that underwent surgery, but did not receive chemerin treatment, a slight raise in inflammatory cell infiltration and increased levels of inflammatory factors were observed compared with rats that did not undergo surgery; however, Secretion of downstream inflammatory cytokines IL-6, MMP-3, MMP-13, and IL-1β was significantly increased in chemerin treated groups compared with control and chemerin + PD98059 groups. In conclusion, the findings of the present study suggested that chemerin may enhance the production of inflammatory factors in synoviocytes by activating the MEK/ERK signaling pathway.

Beyond mechanical loading: The metabolic contribution of obesity in osteoarthritis unveils novel therapeutic targets

“…For example, leptin, chemerin, resistin, visfatin and lipocalin-2 are now believed to have detrimental effects on joint tissue. However, others were reported to maintain cartilage integrity and reduce osteophyte formation, such as progranulin, vaspin and omentin-1 [ 38 , 39 , 95 , [100] , [101] , [102] , [103] , [104] , [105] ]. Accordingly, adipokines have emerged as potential candidates to link obesity with OA which may also serve as putative targets for disease-modifying OA drugs, especially for obese patients [ 95 , 96 , 99 , 103 , 106 ].…”

“… • Activates TLR4 and Akt/ERK pathways. Eisinger et al [ 113 ] Ma et al [ 114 ] Wang et al [ 104 ] Resistin • Binds to TLR4 and CAP1 receptors, which activate p38-MAPK and NF-κB, and C/EBP-β signalling pathways. • Promotes the release of pro-inflammatory cytokines/chemokines and degradative markers such as IL-6, IL-1α, IL-1β, TNF-α, CCL2, CCL3, CCL3L1, CCL4, CCL5, CCL8, CCL20, CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL8 (IL-8), CX3CL1, MMP-1, MMP-13, and ADAMTS-4.…”