Elevated leptin levels in temporomandibular joint osteoarthritis promote proinflammatory cytokine IL-6 expression in synovial fibroblasts.

Leptin, through binding to its special receptor (Ob-Rb), has potent effects on immunity and inflammation. This study measured the levels of leptin in the synovial fluid of patients with temporomandibular joint osteoarthritis (TMJ-OA) and healthy controls, determined the expression of Ob-Rb and explored the effects and signalling pathways involved in leptin-induced proinflammatory cytokine interleukin (IL)-6 production in TMJ synovial fibroblasts (TMJ-SFs). Synovial fluid samples were obtained from 16 patients with TMJ-OA and seven healthy controls. Leptin levels were measured in synovial fluid using enzyme-linked immunosorbent assay (ELISA). Ob-Rb expression was determined by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot in cultured TMJ-SFs. Small interfering RNA (siRNA) was transfected into the TMJ-SFs to down-regulate the expression of Ob-Rb. qRT-PCR and ELISA were used to determine the levels of proinflammatory cytokine IL-6 in leptin-stimulated TMJ-SFs. The involved signalling pathways that mediate the leptin-stimulated production of IL-6 were investigated using specific signalling inhibitor analyses. Compared with healthy controls, patients with TMJ-OA had significantly higher concentrations of leptin in their synovial fluid. The expression levels of Ob-Rb mRNA and proteins were detected in the TMJ-SFs. Leptin can stimulate the mRNA and protein expression of IL-6 in TMJ-SFs by binding with Ob-Rb. The leptin-induced production of IL-6 by the TMJ-SFs significantly decreased after exposure to siRNA targeting Ob-Rb. Inhibiting JAK2/STAT3, p38 MAPK or PI3K/Akt substantially decreased leptin-induced IL-6 production. Leptin may up-regulate IL-6 production in vitro by binding with Ob-Rb in TMJ-SFs via the activation of the JAK2/STAT3, p38 MAPK or PI3K/Akt signalling pathways.

Xiong H ，Li W ，Li J ，Fang W ，Ke J ，Li B ，Cheng Y ，Wei L ... -  《-》

Leptin induces IL-6 and IL-8 expression through leptin receptor Ob-Rb in human dental pulp fibroblasts.

Wei L ，Chen Y ，Zhang C ，Liu M ，Xiong H ... -  《-》

Leptin stimulates interleukin-6 production via janus kinase 2/signal transducer and activator of transcription 3 in rheumatoid synovial fibroblasts.

Muraoka S ，Kusunoki N ，Takahashi H ，Tsuchiya K ，Kawai S ... -  《CLINICAL AND EXPERIMENTAL RHEUMATOLOGY》

Selective glucocorticoid receptor modulator compound A, in contrast to prednisolone, does not induce leptin or the leptin receptor in human osteoarthritis synovial fibroblasts.

Glucocorticoids are powerful anti-inflammatory compounds that also induce the expression of leptin and leptin receptor (Ob-R) in synovial fibroblasts through TGF-βsignalling and Smad1/5 phosphorylation. Compound A (CpdA), a selective glucocorticoid receptor agonist, reduces inflammation in murine arthritis models and does not induce diabetes or osteoporosis, thus offering an improved risk:benefit ratio in comparison with glucocorticoids. Due to the detrimental role of leptin in OA pathogenesis, we sought to determine whether CpdA also induced leptin and Ob-R protein expression as observed with prednisolone. Human synovial fibroblasts and chondrocytes were isolated from the synovium and cartilage of OA patients after joint surgery. The cells were treated with prednisolone, TGF-β1, TNF-α and/or CpdA. Levels of leptin, IL-6, IL-8, MMP-1 and MMP-3 were measured by ELISA and expression levels of Ob-R phospho-Smad1/5, phospho-Smad2, α-tubulin and glyceraldehyde 3-phosphate dehydrogenase were analysed by western blotting. CpdA, unlike prednisolone, did not induce leptin secretion or Ob-R protein expression in OA synovial fibroblasts. Moreover, CpdA decreased endogenous Ob-R expression and down-regulated prednisolone-induced leptin secretion and Ob-R expression. Mechanistically, CpdA, unlike prednisolone, did not induce Smad1/5 phosphorylation. CpdA, similarly to prednisolone, down-regulated endogenous and TNF-α-induced IL-6, IL-8, MMP-1 and MMP-3 protein secretion. The dissociative effect of CpdA was confirmed using chondrocytes with no induction of leptin secretion, but with a significant decrease in IL-6, IL-8, MMP-1 and MMP-3 protein secretion. CpdA, unlike prednisolone, did not induce leptin or Ob-R in human OA synovial fibroblasts, thereby demonstrating an improved risk:benefit ratio.

Malaise O ，Relic B ，Quesada-Calvo F ，Charlier E ，Zeddou M ，Neuville S ，Gillet P ，Louis E ，de Seny D ，Malaise MG ... -  《-》

Pressure and inflammatory stimulation induced increase of cadherin-11 is mediated by PI3K/Akt pathway in synovial fibroblasts from temporomandibular joint.

The goal of the study was to investigate the expression of cadherin-11 in synovial fibroblasts (SFs) under mechanical or inflammatory stimuli, and its potential relationship with PI3K/Akt signaling pathway. SFs separated from rat temporomandibular joint (TMJ) were treated with hydrostatic pressures (HP) of 30, 60, 90, and 120 kPa, as well as tumor necrosis factor-α (TNF-α) for 12, 24, 48, and 72 h. The location of cadherin-11 was observed by immunofluorescence microscopy, and its expression was detected by real-time PCR and Western blot. We also studied the activation of PI3K/Akt signaling pathway in SFs with HP or TNF-α stimulation. The results showed that increased expression of cadherin-11 could be found in the cell-cell contact site of SFs in response to HP and inflammatory stimulation. The mRNA and protein expression of cadherin-11 was positively correlated with the intensity of HP and the duration time of TNF-α treatment. Increased expression of vascular endothelial growth factor-D (VEGF-D) and activation of Akt were also found. Treatment with PI3K inhibitor LY294002 attenuated the pressure or inflammatory cytokine induction increases of cadherin-11, VEGF-D, and FGF-2 both in mRNA and protein levels. These findings suggest that cadherin-11 may play important roles in SFs following exposure to mechanical loading and inflammatory stimulation. In addition, PI3K/Akt pathway was associated with pressure or inflammation-induced cadherin-11 expression, which may involve in the pathogenesis of temporomandibular diseases.

Wu M ，Xu T ，Zhou Y ，Lu H ，Gu Z ... -  《-》