雷奈酸锶治疗人工关节磨损颗粒诱导骨溶解的实验研究

Role of strontium ranelate in Co-Cr-Mo particle-induced osteolysis

目的研究雷奈酸锶治疗人工关节磨损微粒诱导骨溶解的作用,探讨防治人工关节置换术后假体松动的可能性。方法采用小鼠建立Co-Cr-Mo微粒诱导骨溶解的颅骨模型,分为4组:A组为空白组,B组为颗粒对照组,C组为低剂量治疗组,D组为高剂量治疗组。28 d后取出颅骨进行HE染色观察颅骨骨溶解面积,通过ELISA方法检测TNF-α和RANKL的表达,q RT-PCR方法检测RANKL和OPG的表达并分析RANKL/OPG比率变化。结果雷奈酸锶可以明显抑制微粒诱导的骨溶解,对下调TNF-α和RANKL蛋白有确切的疗效,而且这种改变与雷奈酸锶的剂量有关。虽然其对OPG基因转录的抑制作用不太明显,但是对RANKL基因转录和RANKL/OPG基因转录比率的调节与HE染色切片上骨溶解程度相一致。结论雷奈酸锶能够抑制小鼠颅骨骨溶解模型中TNF-α和RANKL的表达,并下调RANKL/OPG基因转录比率,从而抑制了由微粒诱导的骨溶解,为临床预防人工关节置换术后假体松动提供了理论依据。

Objective To evaluate the influence of strontium ranelate on experimental particle-induced osteolysis. Methods Co-Cr-Mo particles were implanted onto the calvaria of particle group B, lower dose treatment group C, and higher dose treatment group D. The other 13 mice were randomly selected as normal control group A. After 28 days, three skulls per group were analyzed using histomorphometry. Five ealvarias per group were prepared for the assay of TNF-a and receptor activator of the nuclear factor κB （RANKL） secretion using quantitative ELISA. The expression of RANKL and osteoprotegerin（OPG） mRNA were evaluated using quantitative real-time PCR. Results As assessed by histomorphometry, Co-Cr-Mo particles induced extensive bone resorption and an intense inflammatory reaction in group B and group C, but not in the group D. In group B and group C, Co-Cr-Mo particles induced an increase in TNF-a and RANKL local concentrations, and resulted in a significant increase in RANKL/OPG messenger RNA （mRNA） ratio. Conversely, these parameters remained unchanged in higher dose treatment group after Co-Cr-Mo implantation. Conclusion Strontium ranelate in the osteolysis murine model ultimately can attenuate osteolytic response to Co-Cr-Mo particles, suggesting a protective effect. This phenomenon is associated with a down-regulation of pro-resorptive cytokines. It is hypothesized that excessive inflammatory response is controlled, illustrated by the absence of increase of TNF-a and RANKL in higher dose treatment mice after Co-Cr-Mo implantation.