雌激素-低氧交互在下颌髁突OA新血管生成中的作用机制研究

Vascularization of articular cartilage is an important pathological basis and new treatment target for OA. However, the detailed mechanism of neovascularization in OA process remains unclear. Both estrogen level changes and hypoxia have close relationship with the development of OA and neovascularization. It has been proved that estrogen-hypoxia crosstalk play an important role in neovascularization in the development of endometrial cancer. However, in literature, no study focused on the effect of estrogen-hypoxia crosstalk on neovascularization in the development of OA. Based on our high-emulational mandibular condylar OA animal model, our previous researches found that neovascularization in condyle increased significantly during OA process in female animals, along with the synchronous high expression of hypoxia-inducible factor (HIF)1α, 2α and VEGF in mandibular condylar cartilage. In the present project, our unique mandibular condylar OA animal model and IL-1β/Flexcell mechanics loading system will be used to simulate OA process in vivo and in vitro. Under different estrogen and HIF level, the expression of ER, HIF, VEGF and other agiogenesis-related factors will be detected, and neovascularization in condyle and OA grading will be analysed synchronously to investigate the effect of estrogen-hypoxia crosstalk on the neovascularization in condyle during OA process. Furthermore, specific blocking test, luciferase reporter assay and ChIP will be employed to investigate its detailed mechanism. The present project will help to clarify the mechanism of OA process, and provide new clues for the prevention and treatment of OA.

关节软骨血管化是OA的重要病理学基础和治疗新靶点，但目前OA新血管生成的具体机制尚不清楚。雌激素水平变化、低氧均与OA的发生发展及新血管生成密切相关，研究证实雌激素与低氧交互在子宫内膜癌等新血管生成中发挥着关键作用，目前尚未见到雌激素-低氧交互在OA新血管生成中作用机制的研究。本课题组前期研究发现雌性动物下颌髁突OA后期髁突软骨血管化明显加速，且HIF1α、2α与VEGF表达同步增高。本项目拟利用独创的下颌髁突OA动物模型和IL-1β/Flexcell力学加载系统在体内、外模拟OA进程，通过对不同雌激素、HIF环境下ER、HIF和VEGF等血管生成因子的表达，及髁突OA新血管生成和OA严重程度的同步检测，探讨雌激素-低氧交互在髁突OA新血管生成中的作用机理，并通过特异性阻断、荧光素酶报告基因表达、ChIP等方法探讨其具体交互机制，从而进一步阐明OA的发生机制，为OA的早期防治提供新思路。

雌激素水平变化、低氧均与OA的发生发展及新血管生成密切相关，以往研究证实雌激素与低氧交互在子宫内膜癌等新血管生成中发挥着关键作用，但未见到雌激素-低氧交互在骨及OA新血管生成中作用机制的研究。本项目依托本课题组特色的下颌髁突OA动物模型和IL-1β/Flexcell力学加载系统在体内外模拟OA进程，通过对不同雌激素、HIF环境下ER、HIF、VEGF等血管生成因子表达，及髁突OA新血管生成和OA严重程度的同步检测，系统探讨了雌激素-低氧交互在髁突OA进程中的作用机理。研究结果证实，不同水平的雌激素、低氧环境对髁突OA的进程与转归具有重要影响，过高、过低的雌激素均不利于髁突稳态的维持，且高生理水平雌激素对髁突软骨、软骨下骨的病程转归具有不同的影响（加重软骨病变、减轻软骨下骨病变）；雌激素可以通过ER-HIF通路上调髁突软骨内HIFs及HIFs下游包括新血管生成因子、软骨基质降解因子等在内的相关因子的表达变化，促进软骨基质降解、软骨下新血管形成，进而加速OA的进程，阻断ER或HIF的效应可有效逆转相关反应。该交互机制的明确对于今后OA的早期干预具有重要意义。

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