YAP在TGF-β信号调控骨关节炎软骨下骨重塑中的作用和机制研究

Osteoarthritis, the major disease that can cause joint pain and disability, has now become a public health issue critical to human health. Subchondral bone remodeling mediated by transforming growth factor-beta (TGF-β) plays an important role in the pathogenesis of osteoarthritis, while the cellular and molecular mechanism of this process remains to be investigated. By integrating with other transcription factors, YAP( yes-associated protein), a transcription coactivator, can regulate the transcriptional activity of target genes, which was also proved to be a key factor mediating TGF-β signal and its biological effects in many cellular and physiological processes. Studies have shown that YAP can promote the osteogenic differentiation of mesenchymal stem cells, as well as the intramembranous ossification of endothelial cells. Meanwhile, it was shown by our previous work that osteoclast differentiation and bone resorption activity could be significantly promoted by YAP and the inhibition of YAP function significantly reduced the bone loss in OVX mice. Since high consistency was shown between the regulation of YAP and TGF-β signal in subchondral bone cells, we speculate that YAP was involved in TGF-β signal-mediated osteoarthritic subchondral bone remodeling. The aim of this project is to investigate the function and mechanism of YAP in the regulation of subchondral bone remodeling mediated by TGF-β signal at the cellular and animal levels, and probe into the feasibility of prevention and treatment of osteoarthritis by regulating YAP activity, in order to provide novel theory and practical basis for osteoarthritis prevention and treatment.

骨关节炎是导致关节疼痛和残障的主要疾病，已成为严重危害人类健康的公共卫生问题。TGF-β信号介导的软骨下骨重塑在骨关节炎发病过程中至关重要，但其细胞和分子机制还有待研究。YAP是一个转录共激活因子，通过与其他转录因子结合调控靶基因的转录活性，在多种细胞和生理进程中被证实是介导TGF-β信号的关键因子。已有研究表明，YAP能促进间充质干细胞向成骨细胞分化，并能促进内皮细胞膜内成骨。我们的前期研究发现，YAP亦能促进破骨细胞分化成熟和蚀骨活性，抑制YAP的功能明显减少卵巢切除小鼠的骨量丢失。鉴于YAP与TGF-β信号的密切联系及其对软骨下骨各型细胞的调控作用与TGF-β信号高度吻合，我们推测YAP参与了TGF-β促进骨关节炎软骨下骨重塑的过程。本项目拟在细胞与动物水平对其相互作用和机制进行研究，并初步探讨通过调节YAP活性缓解骨关节炎的可行性，以期为骨关节炎防治提供新的理论和实践依据。

研究背景：骨关节炎是导致关节疼痛和残障的主要疾病，已成为严重危害人类健康的公共卫生问题。TGF-β信号介导的软骨下骨重塑在骨关节炎发病过程中至关重要，但其细胞和分子机制还有待研究。YAP是一个转录共激活因子，通过与其他转录因子结合调控靶基因的转录活性，在多种细胞和生理进程中被证实是介导TGF-β信号的关键因子。我们的前期研究发现，YAP能促进破骨细胞分化成熟和蚀骨活性，抑制YAP的功能明显减少卵巢切除小鼠的骨量丢失。本项目拟在细胞与动物水平对其相互作用和机制进行研究，并初步探讨通过调节YAP活性缓解骨关节炎的可行性，以期为骨关节炎防治提供新的理论和实践依据。.研究内容：（1） YAP 活性对成骨和破骨系细胞分化成熟的影响。（2） TGF-β 在成骨和破骨系细胞分化成熟过程中对 YAP 活性的调控作用。（3） YAP 在 TGF-β 调控成骨和破骨系细胞分化和活性中的作用。（4）骨关节炎动物模型软骨下骨组织细胞中 YAP 的活性变化。（5）调控 YAP 活性改善骨关节炎软骨下骨重塑和整体病情的可行性。.重要结果及关键数据：（1）YAP在体外模拟炎症环境下表达降低；（2）YAP在体外模型中具有促炎作用；（3）IL-1β刺激YAP核转移从而使其发挥作用；（4）YAP通过NF-κB和MAPK通路调节软骨炎症；（5）YAP在破骨分化中表达减少；（6）YAP促进破骨细胞分化和形成；（7）YAP通过与TEAD以及AP1结合调控破骨分化；（8）YAP还通过NK-κB通路调节破骨分化；（9）抑制YAP可以减少骨质疏松引起的骨量减少。.科学意义：该项目研究结果证明YAP在骨性关节炎和骨质疏松中起重要作用，抑制YAP可以减轻炎症，抑制破骨分化和形成，减少骨质疏松引起的骨量减少，并从机制上进行了探究，为以后骨性关节炎和骨质疏松的新药制备和临床治疗提供了新的思路和依据。