类风湿关节炎患者血清中高迁移率族蛋白1的作用及其与MMP2、TIMP2的关系

Role of HMGB1 in rheumatoid arthritis patients and its correlation with expression of MMP2 and TIMP2

目的初步探讨高迁移率族蛋白(HMGB)1、基质金属蛋白酶(MMP)2及其组织抑制因子(TIMP)2在类风湿关节炎(RA)中的作用及可能作用机制。方法收集61例RA患者和24例健康志愿者外周血。采用ELISA方法检测血清中HMGB1、MMP2和TIMP2蛋白表达量。采用流式细胞术分析外周血单个核细胞(PBMC)表面Toll样受体(TLR)4和CD147的表达。同期进行ESR、CRP、RF和双手正位X线检查等相关指标检测。结果RA患者血清中,HMGB1浓度较健康对照组显著升高([9.34±2.25vs7.40±1.06)ng.mL-1](]P<0.01),而MMP2和TIMP2浓度明显低于健康对照组(571.26±81.95vs633.76±26.92)和(259.27±18.90vs273.85±26.31)(P<0.01和P<0.05)。PBMC中TLR4+CD147+和CD14+CD147+细胞比例和平均荧光强度显著高于健康对照组(P<0.01)。HMGB1水平与ESR、CRP、RF及X线分期均呈正相关(P<0.05或P<0.01),亦与CD14+CD147+和TLR4+CD147+的平均荧光强度呈显著正相关(P<0.01)。而MMP2水平与之呈负相关(P<0.05和P<0.01)。结论胞外HMGB1通过激活PBMC表达粘附分子CD147而发挥其致炎效应,并直接或间接下调了保护性因子MMP2的表达,加速关节炎进展。HMGB1可能成为RA治疗新靶点。

【Objective】To investigate the role and possible mechanism of high mobility group box（HMGB） 1,matrix metalloproteinase（MMP） 2 and tissue inhibitor of MMP（TIMP） 2 in rheumatoid arthritis（RA）.【Methods】 Peripheral blood mononuclear cell（PBMC） and serum samples were obtained from 61 RA patients and 24 health controls.Serum concentration of HMGB1,MMP2 and TIMP2 was detected by ELISA.Flow cytometry analysis was used to detect the expression of Toll-like receptor（TLR） 4 and CD147 on PBMC.Clinical indexes of ESR,CRP,RF and X-ray phases were recorded.【Results】The concentration of HMGB1 in RA patients was significantly higher than that in health controls [（9.34±2.25） ng.mL-1 vs（7.40±1.06） ng.mL-1,P 0.01].Reversely,concentrations of MMP2 and TIMP2 in RA patients were significantly lower compared with those in health controls,respectively [（571.26±81.95） vs（633.76±26.92）,（259.27±18.90） vs（273.85±26.31）,P0.05].Cell clusters of TLR4＋ CD147＋ and CD14＋ CD147＋ in PBMC of RA patients were significantly increased than those in healthy controls,so did the MFI（P0.01）.Level of HMGB1 protein was positively correlated with ESR,CRP,RF,radiographic phase,so did it with MFI of TLR4＋ CD147＋ and CD14＋ CD147＋.While the levels of MMP2 and TIMP2 were negatively correlated with MFI of TLR4＋ CD147＋ and CD14＋ CD147＋（P0.05）.【Conclusion】Our data suggested that HMGB1 protein,once released from certain cells,could activate PBMC and exhibit pro-inflammatory effects by up-regulating CD147 expression and down-regulating protective factor MMP2 expression.HMGB1 may be a new potential therapeutic target in RA.