探究不同剂量辛伐他汀对肋骨骨折大鼠骨组织愈合的影响及其机制，选取60只SPF级SD大鼠建立大鼠肋骨骨折模型，随机分为对照组(n=15)、辛伐他汀低剂量组(n=15)，辛伐他汀中剂量组(n=15)、辛伐他汀高剂量组(n=15)。辛伐他汀处理组大鼠造模后分别采用辛伐他汀2。5、5。0、10。0 mg/(kg·d)灌胃，连续4周，于实验终点采用小动物活体成像系统检测肋骨愈合情况;HE染色确定肋骨病理变化;酶联免疫吸附测定(ELISA)检测各组大鼠外周血白细胞介素(interleukin，1L)-1、IL-17、肿瘤坏死因子-α(tumor necrosis factor-α，TNF-α)、骨代谢分子骨保护素(osteoclastogenesis inhibitory factor，OPG)及核因子 κ B 受体活化因子配体(receptor activator of nuclear factor-K B ligand，RANKL)表达水平的变化;蛋白电泳检测成骨细胞骨钙素(osteocalcin，OCN)、Runx2蛋白的表达。小动物活体成像结果显示辛伐他汀低剂量组、辛伐他汀中剂量组和辛伐他汀高剂量组大鼠骨骼愈合优于对照组，并且随着辛伐他汀用量的提高愈合程度提高;HE染色结果表明辛伐他汀低剂量组、辛伐他汀中剂量组和辛伐他汀高剂量组大鼠骨排列方向较为一致，炎性细胞浸润减少，并且随着辛伐他汀用量的提高病理损伤程度降低;ELISA结果表明辛伐他汀低剂量组、辛伐他汀中剂量组和辛伐他汀高剂量组大鼠血清IL-1、IL-17及TNF-α表达水平显著升高，骨代谢相关分子OPG、RANKL表达水平显著升高，OPG/RANKL比值也显著升高，并且随着辛伐他汀使用的剂量增加显著增加，差异具有显著的统计学意义(P＜0。01)。蛋白电泳结果显示，与对照组比较，不同剂量辛伐他汀组大鼠OCN、Runx2蛋白表达水平显著升高，并且随着辛伐他汀使用的剂量增加显著增加，差异具有显著的统计学意义(P＜0。01)。辛伐他汀对大鼠骨折愈合有促进作用，其机制可能与促进炎症因子释放、激活成骨信号通路OPG/RANKL、骨细胞活性有关。
Effect of Simvastatin on Bone Healing in Rat Model of Ribfracture and its Mechanism
In order to investgate the effects of different doses of simvastatin on bone tissue healing in rats with rib fractures and its mechanism,60 SPF grade SD rats were selected to establish a rat rib fracture model and randomly divided into control group(n=15),simvastatin low dose group(n=15),simvastatin medium dose group(n=15)and simvastatin high dose group(n=15).Sim-vastatin-treated rats were gavaged with 2.5,5 and 10 mg/(kg·d)for 4 weeks after modelling,and rib healing was detected at the endpoint of the experiment using a small-animal live imaging system;HE staining was used to determine pathological changes in ribs;Enzyme-linked immunosorbent assay(ELISA)was performed to detect changes in peripheral blood levels of interleukin(IL)-1,IL-17,tumour necrosis factor-α(TNF-α),osteoclastogenesis inhibitory factor(OPG),and receptor activator of nuclear factor-KB ligand(RANKL)in all groups of rats.Osteocalcin(OCN)and Runx2 protein expression in osteoblasts were detected by protein electro-phoresis.Small-animal biopsy results showed that rats in the simvastatin low-dose,simvastatin medium-dose and simvastatin high-dose groups had better bone healing than the control group,and the degree of healing increased as simvastatin dosage was increased;the results of HE staining showed that rats in the simvastatin low-dose group,simvastatin medium-dose group and simvastatin high-dose group had a more consistent direction of bone alignment,with a reduction in inflammatory cell infiltration,and the degree of pathological damage was reduced with the increasing in the dosage of simvastatin;ELISA results showed that the expression levels of serum IL-1,IL-17 and TNF-α were significantly increased in the simvastatin low-dose,simvastatin medium-dose and simvastatin high-dose groups of rats,and the expression levels of bone metabolism-related molecules OPG and RANKL were significantly increased,as well as the OPG/RANKL ratio,which also significantly increased with the increasing dose of simvastatin used,and the difference was statistically significant(P＜0.01).The results of protein electrophoresis showed that the expression levels of osteocalcin and Runx2 proteins were significantly higher in the rats of different doses of simvastatin group compared with the control group and increased significantly with the increasing of the dose of simvastatin used,and the difference was statistically significant(P＜0.01).Simvastatin can pro-mote fracture healing in rats,and its mechanism may be related to promoting the release of inflammatory cytokines and activating OPG/RANKL osteogenic signal pathway and osteoblast activity.
SimvastatinFractureInflammatory factorsOPG/RANKL signal pathwayBone healingMechanismsRat model
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