TLR4/NF-κB通路与相关炎症因子在激素性股骨头坏死发生和转归中的机制研究

Glucocorticoid-induced osteonecrosis of the femoral head (ONFH) is closely related with autoimmune diseases and inflammation, which mediates destruction, reparation and remodeling of bone structure. Toll-like receptor 4 (TLR4) is able to bind to various ligands, such as LPS, to induce respective inflammation factors through NF-κB pathway, to modulate bone homeostasis. In the current study, we hypothesized that inflammation and underlying TLR4/NF-κB pathway regulated development and advancement of glucocorticoid-induced ONFH. In in vitro studies, we will use glucocorticoid to treat bone and vascular precursor cells, to observe the expression of NF-κB regulated by TLR4, and to investigate cell proliferation, differentiation and apoptosis. Moreover, we will employ specially-made chip to detect TLR4 and downstream inflammatory factors, to analyze relativity between inflammation activity and cellular behavior. In in vivo studies, we will make animal model of glucocorticoid-induced ONFH in wild-type and TLR4-deleted mice. The progression of ONFH is monitored by in vivo imaging techniques. For the harvested specimen of blood and femoral head, pathologic, cellular and immunological methods will be used to assess the expression and distribution of interesting inflammation factors. Based on above-mentioned in vitro and in vivo studies, we will target and interfere with the inflammation activity, to assess the effect on the prevention of glucocorticoid-induced ONFH. The current study will confirm TLR4/ NF-κB pathway in the inflammation as a core role in the pathogenesis of glucocorticoid-induced ONFH.

激素性股骨头坏死和自身免疫性疾病及炎症密切相关，炎症介导了骨破坏、修复和重构等重要过程。TLR4能与LPS等配体结合，经NF-κB通路，诱导炎症因子表达、参与骨稳态。本研究中，我们提出假说：炎症及TLR4/NF-κB通路调控激素性股骨头坏死的发生和转归。体外实验中，我们应用激素干预骨和血管内皮前体细胞，观察调控TLR4对NF-κB的表达以及细胞增殖、分化和凋亡的影响；芯片定量分析TLR4下游炎症分子，分析其与细胞行为的相关性。体内实验中，我们在TLR4完全敲除和野生型小鼠上构建股骨头坏死模型，动态成像观察坏死进展，获取外周血和股骨头标本，采用病理学、细胞学和免疫学方法检测外周血和股骨头中炎性分子表达和分布。基于体外和体内实验结果，我们通过炎症靶向干预手段，观察其对激素性股骨头坏死的防治结果。通过本研究，可明确以TLR4/NF-κB为核心的炎症反应在激素性股骨头坏死发生和转归中担任重要作用。

激素性股骨头坏死和自身免疫性疾病及炎症密切相关，炎症介导了骨破坏、修复和重构等重要过程。TLR4能与LPS等配体结合，经NF-κB通路，诱导炎症因子表达、参与骨稳态。本研究中，我们提出假说：炎症及TLR4/NF-κB通路调控激素性股骨头坏死的发生和转归。体外实验中，我们应用激素干预骨和血管内皮前体细胞，观察炎症表达对细胞增殖、分化和凋亡的影响；采用炎症因子芯片定量分析TLR4下游炎症分子表达情况，分析其与细胞行为的相关性。体内实验中，我们建立多种股骨头坏死模型，动态成像观察坏死进展，获取外周血和股骨头标本，采用病理学、细胞学和免疫学方法检测外周血和股骨头中炎性分子表达和分布。本研究发现，糖皮质激素可引起骨髓来源经典型单核细胞增多和破骨细胞分化相关基因表达，单核细胞缺失则可恢复激素介导的骨量丢失；IL-17，JAK-STAT通路同激素性股骨头坏死关系较密切，而IL-17A可能发挥着核心作用；毛蕊异黄酮可通过干预TLR/NF-κB通路，降低炎症因子的分泌，并促进骨再生，从而减少股骨头坏死的发生率。通过本研究，可明确以TLR4/NF-κB为核心的炎症反应在激素性股骨头坏死发生和转归中担任重要作用。

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