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Aim To investigate the effects of DAP on human rheumatoid arthritis synovial fibroblasts(RA-FLS)and its relationship with endoplasmic reticulum stress(ERS)PERK/ATF4/CHOP signaling pathway.Methods RA-FLS cells were cultured and identified by immunofluorescence assay for Vimentin and CD68.CCK-8 detected(0,5,10,20,30,40,50,60,70)mg·L-1 DAP on the proliferation activity of RA-FLS cells.According to the proliferation activity,the experiment was divided into blank group(Blank),low dose group(L-DAP),medium dose group(M-DAP),high dose group(H-DAP)and high dose+specific inhibitor 4-PBA group(H-DAP+4-PBA).The levels of TNF-α and IL-6 were detected by ELISA.Cell apoptosis was detected by flow cytometry.The invasion and migration of cells were detected by Transwell and scratches assays,and the expressions of endoplasmic reticulum stress-related proteins GRP78,PERK,P-PERK,ATF4,CHOP,Caspase-12,C-Caspase-12 and Bcl-2 were assessed by Western blot.Results CCK-8 results showed that compared with 0 mg·L-1 DAP group,the proliferation activity of each group in 20-70 mg·L-1 DAP group was significantly different(P<0.05),and the proliferation rate corresponding to 0,20,40 and 60 mg·L-1 DAP group was significantly different(P<0.05).This concentration was used as the basis for blank,low-dose,medium-dose,high-dose groups and high-dose+4-PBA experimental grouping.DAP could inhibit the release of inflammatory cytokines IL-6 and TNF-α from RA-FLS cells in concentration,reduce the invasion ability of cells,promote apoptosis,upregulate the expression of PERK,P-PERK,ATF4,GRP78,CHOP,Caspase-12, C-caspase-12 proteins and decrease the expression level of anti-apoptotic protein Bcl-2.Another set of experiments demonstrated that high dose DAP+4-PBA could up-regulate the expression of IL-6 and TNF-α,as well as the invasion of cells,and inhibit the expression of apoptosis and ERs-related proteins.Conclusions Daphresin regulates the secretion of inflammatory factors by activating the PERK/ATF4/CHOP signaling pathway,inhibits the proliferation and invasion of RA-FLS cells,and induces apoptosis,which is expected to be a potential therapeutic pathway for RA.
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BACKGROUND@#Clinical outcomes of undifferentiated arthritis (UA) are diverse, and only 40% of patients with UA develop rheumatoid arthritis (RA) after 3 years. Discovering predictive markers at disease onset for further intervention is critical. Therefore, our objective was to analyze the clinical outcomes of UA and ascertain the predictors for RA development.@*METHODS@#We performed a prospective, multi-center study from January 2013 to October 2016 among Chinese patients diagnosed with UA in 22 tertiary-care hospitals. Clinical and serological parameters were obtained at recruitment. Follow-up was undertaken in all patients every 12 weeks for 2 years. Predictive factors of disease progression were identified using multivariate Cox proportional hazards regression.@*RESULTS@#A total of 234 patients were recruited in this study, and 17 (7.3%) patients failed to follow up during the study. Among the 217 patients who completed the study, 83 (38.2%) patients went into remission. UA patients who developed RA had a higher rheumatoid factor (RF)-positivity (42.9% vs. 16.8%, χ = 8.228, P = 0.008), anti-cyclic citrullinated peptide (CCP) antibody-positivity (66.7% vs. 10.7%, χ = 43.897, P < 0.001), and double-positivity rate of RF and anti-CCP antibody (38.1% vs. 4.1%, χ = 32.131, P < 0.001) than those who did not. Anti-CCP antibody but not RF was an independent predictor for RA development (hazard ratio 18.017, 95% confidence interval: 5.803-55.938; P < 0.001).@*CONCLUSION@#As an independent predictor of RA, anti-CCP antibody should be tested at disease onset in all patients with UA.
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Objective To observe the expressions of bone morphogenetic protein-2(BMP-2)and bone morphogenetie protein-7(BMP-7)in the synovial tissue of fluorosis rats and its correlation with pathogenic mechanism of fluorosis arthritis.Methods Thirty-two SD rats were randomly divided into 4 groups:the control group,low,moderate and high-dose fluoride group.The control group ate commou fodder.The low,moderate and high dose fluoride group were fed with fodder composed of 25%.35%and 68%of corn(containing fluorine of 148.00 mg/kg)in chronic endemic fluorosis region in Guizhou Province.After 140 days,the expressions of BMP-2 and BMP-7 protein were determined by immunohistochemistry and assayed the absorbanee by computer image-pattern analysis system.Light microscope was used to observe the synovial tissue by Hematoxin Eosin,and calculated the pathological integral of synovium according to pathological grade standard.Results The expressions of BMP-2 (32.50±2.73)and BMP-7(38.90±2.56)in the control group was spare.Compared with the control group,the expressions of BMP-2(59.43±5.12,79.82±6.41,101.76±7.56)and BMP-7(55.10±4.82,78.42±5.61,98.46± 6.05)in the synovial tissue was up-regulated in each experimental groups(P＜0.05),especially in the moderate dose and the high-dose groups(P＜0.05).Compared with the control group(0.54±0.21).the pathological integral of synovium increased(P＜0.05)in each experimental groups(1.04±0.98,4.69±1.28,8.60±2.07).The expressions of BMP-2 and BMP-7 in the synovial tissue was found to be positively related with the pathological integral of synovium(r=0.98,0.99,P＜0.05).Conclusion The BMP-2 and BMP-7 play an important role in the development of fluorosis arthritis,probably by affecting osteogenesis.