杨梅素通过PPARγ/TLR4通路调控巨噬细胞极化用于假体周围骨溶解治疗的研究

Local inflammatory reaction and bone metabolism disorder caused by macrophage M1 polarization is am important mechanism of wear particles-induced periprosthetical osteolysis. Our previous studies showed myricetin，a flavonol compound, can inhibit wear particles-induced osteolysis partly through suppressing osteoclast differentiation and inhibit the release of inflammatory cytokines by M1 macrophage. Accordingly, myricetin may be involved in the regulation of macrophage polarization directly, but the molecular mechanism is still unknown. TLR4 (Toll-like receptor 4 ) pathway plays a key role in the process of M1 macrophages polarization. We also found that myricetin can suppress the activity of MAPK (mitogen-activated protein kinase) and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathway, which are the downstream signaling of TLR4 pathway. Thus, myricetin may regulate macrophage polarization via the TLR4 pathway. Therefore, this project intends to study as follows:①whether myricetin can ameliorate wear particles-induced inflammatory bone imbalance; ②the effect of myricetin on wear particles-induced macrophage polarization; ③the regulatory mechanism of myricetin on TLR4 pathway. According to the previous studies, we speculated that myricetin may regulate macrophage polarization through suppressing TLR4 pathway by increasing PPARγ (Peroxisome proliferator-activated receptor γ) expression. In addition, we constructed nanospheres controlled- release myricetin to improve administration route and therapeutic effect by targeting bone tissue specially. Collectively, this study will provide more evidences for clinical prevention and treatment of periprosthetical osteolysis by myricetin.

巨噬细胞M1型极化能导致局部炎性骨代谢失衡，是磨损颗粒诱导假体周围骨溶解的重要机制。申请人发现，黄酮类中药单体杨梅素能够抑制单核巨噬细胞向破骨细胞分化，部分解释其对磨损颗粒诱导骨溶解的治疗作用。同时，杨梅素能够抑制M1型巨噬细胞炎症因子释放，提示杨梅素可能直接参与调控巨噬细胞极化过程，但机制不明。TLR4是介导巨噬细胞M1型极化的重要通路。预实验发现，杨梅素能够抑制TLR4下游MAPK/NF-κB活性。提示，杨梅素可能通过TLR4通路调控巨噬细胞极化。因此，本项目拟研究杨梅素①对磨损颗粒诱导炎性骨失衡的调控作用；②对磨损颗粒诱导巨噬细胞极化的调控作用；③对TLR4通路的调控作用机制。结合前期研究推测，杨梅素可能通过促进PPARγ表达，抑制TLR4通路从而调控巨噬细胞极化。此外，构建骨靶向杨梅素缓释微球，以改善给药途径及治疗效果。本研究将为杨梅素防治假体周围骨溶解的临床转化提供更多理论依据。

巨噬细胞M1型极化能导致局部炎性骨代谢失衡，是磨损颗粒诱导假体周围骨溶解的重要机制。黄酮类中药单体杨梅素能够抑制单核巨噬细胞向破骨细胞分化，部分解释其对磨损颗粒诱导骨溶解的治疗作用。同时，杨梅素能够抑制M1型巨噬细胞炎症因子释放，提示杨梅素可能直接参与调控巨噬细胞极化过程，但机制不明。本课题研究发现1）杨梅素抑制磨损颗粒诱导炎性骨失衡作用；2）杨梅素抑制磨损颗粒诱导巨噬细胞极化作用；3）杨梅素通过 PPARγ/TLR4 信号通路调控巨噬细胞极化。综上，杨梅素可能通过促进PPARγ表达，抑制TLR4通路从而调控巨噬细胞极化。此外，通过构建骨靶向杨梅素缓释微球，改善给药途径及治疗效果。本研究为杨梅素防治假体周围骨溶解的临床转化提供更多理论依据。