重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白对胶原诱导性关节炎大鼠骨质及骨保护素的影响

The effect of recombinant human type Ⅱ tumor necrosis factor receptor-antibody fusion protein on bone mineral density and OPG in rats with collagen-induced arthritis

目的研究重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白(rhTNFR:Fc,益赛普)及其他慢作用药对胶原诱导性关节炎大鼠骨密度及骨保护素的影响,探讨各种方案对骨代谢生化指标、骨质的改变。方法建立Ⅱ型胶原诱导的雄性Wistar大鼠CIA模型,随机分为正常对照组、CIA模型对照组、MTX联合强的松龙组、MTX联合羟氯喹和柳氮磺吡啶组、MTX联合益赛普组。分别于第10、21周予行大鼠四肢关节钼靶拍片及测骨保护素(OPG)。结果 CIA组大鼠第10周出现骨质疏松、关节软骨、骨破坏、关节间隙狭窄,MTX+pred组大鼠出现骨质疏松,关节腔结构尚完整,MTX+HCQ+SSZ组大鼠出现骨质疏松、关节软骨、骨轻度破坏、关节间隙轻度狭窄,MTX+rhTNFR:Fc组大鼠则仅出现骨质轻度破坏;第21周时CIA组、MTX+pred组和MTX+HCQ+SSZ组大鼠骨质破坏加重,而MTX+rhTNFR:Fc组大鼠则未见骨质破坏加重。4组血清OPG水平在治疗前均出现降低,第10周时4组OPG水平均出现降低,但MTX+rhTNFR:Fc组降低较其他3组有统计学意义(P<0.05)。21周时CIA组、MTX+pred组和MTX+HCQ+SSZ组OPG水平均出现进一步降低(P<0.05),但MTX+rhTNFR:Fc组未见明显降低(P>0.05)。结论 rhTNFR:Fc能有效抑制胶原诱导性关节炎大鼠骨质破坏,其作用机制可能与OPG相关。

Objective To investigate the effect of recombinant human typeⅡ tumor necrosis factor receptor- antibody fusion protein （rhTNFR： Fc, Etanercept） and other slow-acting drugs on bone mineral density （BMD） and OPG in rats with collagen-induced arthritis （CIA）, and to explore the changes of bone metabolic markers and BMD by the treatments. Methods CIA model induced by type Ⅱ collagen was established in male Wistar rats. The rats were randomly divided into normal control group, CIA model control group, MTX ＋ prednisolone （pred） group, MTX ＋ hydroxychloroquine （HCQ） ＋ sulfasalazine - （SSZ） group, and MTX ＋ rhTNFR ：FC group. Joints molybdenum target X-ray of rat limbs and detection of OPG were performed in 10 weeks and 21 weeks, respectively. Results At the 10th week, rats in CIA group showed osteoporosis, destruction of articular cartilage and bone, and the narrowing of joint space. Rats in MTX ＋ pred group had osteoporosis, but their joint cavity structure was still intact. Rats in MTX ＋ HCQ ＋ SSZ group had osteoporosis, mild destruction of articular cartilage and bone, and mild stenosis of joint space. Rats in MTX ＋ rhTNFR：Fc group only had mild bone destruction. At the 21st week, bone destructionof rats in CIA group, MTX ＋ pred group, and MTX ＋ HCQ ＋ SSZ group aggravated, but there was no aggravation of bone destruction in MTX ＋ rhTNFR： Fc group. Serum OPG levels in all 4 groups decreased before the treatment. They were all decreased at the 10th week, but the serum OPG level in MTX ＋ rhTNFR：Fc group was statistically significant lower than that in the other 3 groups （P 〈 0. 05）. At the 21st week, serum OPG levels in CIA group, MTX ＋ pred group, and MTX ＋ HCQ ＋ SSZ group further decreased （P 〈 0.05） , but there was no significant decrease of serum OPG level in MTX ＋ rhTNFR： Fc group （ P 〉 0.05）. Conclusion RhTNFR：Fc can inhibit the bone destruction in rats with collagen-induced arthritis, and its mechanism may be related to OPG.