雷尼酸锶抑制磨损颗粒诱导小鼠假体周围骨溶解的作用及机制研究

Aseptic loosening is one of the most frequent long-term complications after joint replacement, which is the main reason for artificial joint replacement failure. At present, there is no effective non-surgical treatment for it. Wear particles are phagocytosed by macrophages, resulting in cellular activation and release of proinflammatory factors, which cause the Periprosthetic osteolysis and subsequent aseptic loosening are the most common causes of total joint arthroplasty failure. During this pathologic process,the increased bone absorption and reduced bone formation are involved in periprosthetic osteolysis.The mechanism of prosthetic aseptic loosening and osteoporosis is similar. Therefore, This topic is based on our previous inhibiting bone resorption, proposed has the inhibiting bone resorption, dual function at the same time promote bone formation of strontium ranelate, the prevention and treatment of periprosthetic osteolysis experiments.the purpose of this research is to determine whether the effect of strontium ranelate can inhibit wear particle-induced periprosthetic osteolysis in a mouse model; Then, to investigate whether strontium ranelate can reduce the production of inflammatory cytokines and whether could promote osteoblast differentiation and mineralization in the presence of inflammatory factor. Again, to clear strontium ranelate prevention effect is mainly down-regulation sclerosis expression on the osteoblast, thus activate the Wnt/beta - Catenin signaling pathway, so as to inhibit bone absorption and promoting bone formation, or/and synergistic inhibition of inflammatory factor generated. Further verify the better prevention and treatment of periprosthetic osteolysis by different ways of drug delivery.These will be provide experimental basis for prosthesis loosening in clinical.

无菌性松动是导致人工关节置换术后中晚期失败的主要原因，目前尚无有效的药物治疗方法。磨损颗粒引起炎性因子释放，刺激破骨细胞活化和抑制成骨细胞分化，导致假体周围骨吸收增加，同时骨形成减少是松动发生的重要机制。本课题是在我们前期主要针对抑制骨吸收方面研究的基础上，选用具有抑制骨吸收，同时促进骨形成双重作用的雷尼酸锶，进行防治假体周围骨溶解的实验研究。目的在于确定雷尼酸锶在体内有无防治假体周围骨溶解的作用，探讨雷尼酸锶能否减少炎性因子的产生，能否在炎性因子存在的情况下仍能促进成骨细胞分化，并且明确其作用机制是主要通过下调骨硬化蛋白的表达，从而激活Wnt/β-Catenin信号通路，抑制骨吸收和促进骨形成，还是协同抑制炎性因子生成共同作用所致。进一步验证通过优化给药途径能否提高局部药物浓度，减少全身用药的副作用，从而为药物防治人工关节无菌性松提供新的实验依据

无菌性松动是导致人工关节置换术后中晚期失败的主要原因， 目前尚无有效的药物治疗方法。磨损颗粒引起炎性因子释放，刺激破骨细胞活化和抑制成骨细胞分化， 导致假体周围骨吸收增加， 同时骨形成减少是松动发生的重要机制。本课题首次验证了雷尼酸锶在人工关节无菌性松动预防与治疗方面的功能及对其可能的产生作用机制进行了探讨。体内实验方面，我们建立了胫骨钛钉模型来模拟人工膝关节置换手术，并在此基础上分别在三种模式动物：野生型C57BL6小鼠、骨硬化蛋白SOST基因敲出C57BL6小鼠、老年雌性去卵巢C57BL6小鼠，通过灌胃给药途径验证了雷尼酸锶的药物作用。体外实验方面，我们验证了在钛金属颗粒的刺激下，雷尼酸锶药物对破骨细胞，成骨细胞以及骨髓间充质干细胞的作用影响。特别地，我们建立了钛金属颗粒刺激单核巨噬细胞释放炎症细胞因子，并与成骨细胞共培养的细胞水平人工关节无菌性松动模型。并在此基础上通过分子生物学技术手段验证了雷尼酸锶防治人工关节无菌性松动的功能与可能作用机制。本课题首次揭示了雷尼酸锶防治人工关节无菌性松动是通过下调成骨细胞骨硬化蛋白SOST的表达，进而间接地激活了WNT/β-连环蛋白信号通路来缓解修复磨损颗粒导致的假体周围慢性炎症性骨溶解。