二甲双胍通过AMPK通路介导多重骨代谢平衡调节对超高分子量聚乙烯颗粒诱导骨溶解的防治效果与机制研究

One of the main reasons for the prosthesis failure after total joint arthroplasty is caused by the wear debris induced osteolysis. Osteolysis is came about from macrophages to phagocytosis of wear debris, which can induce the formation of local inflammatory microenvironment and prompt the activation of the osteoclasts, eventually led to the occurrence of osteolysis around prosthesis. The research shows that AMPK has obvious characteristic of bone protective and anti-inflammatory properties through activation. In our previous experiment, we found that significantly reduced the expression of phosphorylated AMPK in periprosthetic membrane taken from the patients suffered from aseptic loosening than those taken from the patients with stable implant fixation. In addition, the ultra high molecular weight polyethylene (UHMWPE) particles were co-cultured in vitro with macrophages, can significantly improve the inflammatory cytokine production, and the activation of AMPK by metformin can significantly inhibit UHMWPE particles induced the production of inflammatory factor, the use of AMPK inhibitors can reverse the inhibitory effect of metformin on inflammatory factors. We hypothesized that metformin could enhance bone formation,inhibit osteoclast and anti-inflammation, with the potential for clinical application perspective in the prevention and cure osteolysis induced by wear debris. The purpose of this study is to investigate the protective effect of metformin on osteolysis and the involved mechanism by a series further experimental study.

磨损碎屑诱导的骨溶解是造成关节置换术后假体失败最主要的原因之一。骨溶解从巨噬细胞对磨屑的吞噬开始，进而诱导局部炎症微环境形成并促使破骨细胞活化，最终导致假体周围骨溶解的发生。研究表明，AMP激活蛋白激酶被活化后具有骨保护及抗炎特性。我们的前期实验发现，假体周围骨溶解患者界膜组织中磷酸化AMPK表达水平较假体固定稳定患者显著降低。此外，将超高分子量聚乙烯（UHMWPE）颗粒在体外与巨噬细胞共培养，可以显著提高炎性因子的产生，而AMPK被二甲双胍激活后可以显著抑制UHMWPE颗粒所诱导的炎性因子产生，使用AMPK抑制剂则可以逆转二甲双胍对炎性因子的抑制效应。我们推测二甲双胍具有促进成骨、抑制破骨以及抗炎的作用，在磨屑所诱导的骨溶解的防治方面具有潜在的临床应用前景。本研究旨在通过进一步实验研究其对骨溶解的保护效应及其中所涉及的可能机制。

磨损碎屑诱导的骨溶解是造成关节置换术后假体失败最主要的原因之一。骨溶解从巨噬细胞对磨屑的吞噬开始，进而诱导局部炎症微环境形成并促使破骨细胞活化，最终导致假体周围骨溶解的发生。研究表明，AMP激活蛋白激酶被活化后具有骨保护及抗炎特性。我们的前期实验发现，假体周围骨溶解患者界膜组织中磷酸化AMPK表达水平较假体固定稳定患者显著降低。此外，将超高分子量聚乙烯（UHMWPE）颗粒在体外与巨噬细胞共培养，可以显著提高炎性因子的产生，而AMPK被二甲双胍激活后可以显著抑制UHMWPE颗粒所诱导的炎性因子产生，使用AMPK抑制剂则可以逆转二甲双胍对炎性因子的抑制效应。我们推测二甲双胍具有促进成骨、抑制破骨以及抗炎的作用，在磨屑所诱导的骨溶解的防治方面具有潜在的临床应用前景。本研究通过进一步实验，揭示了二甲双胍对无菌性松动的可能治疗作用及其机制。通过实验发现，二甲双胍促进巨噬细胞向抗炎表型转变。并且这种抗炎作用与AMPK的活化有关。我们还通过构建体外成熟骨细胞3D培养体系发现，二甲双胍通过调节成熟骨细胞的分泌因子促进成骨细胞增殖分化，抑制破骨细胞形成，并且二甲双胍对OPG的调节作用依赖于AMPK通路。二甲双胍在小鼠颅骨骨溶解模型中通过影响成熟骨细胞分泌，发挥骨保护作用。

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