TMJ骨关节炎退变软骨中Piezo1介导YAP调控软骨细胞向成骨细胞分化的机制研究
结题报告
批准号:
82001071
项目类别:
青年科学基金项目
资助金额:
24.0 万元
负责人:
杨鸿旭
学科分类:
味觉、口颌面疼痛、咬合及颞下颌关节疾病
结题年份:
2023
批准年份:
2020
项目状态:
已结题
项目参与者:
杨鸿旭
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中文摘要
异常生物力是骨关节炎(OA)的主要病因,异常咬合可导致TMJ OA发生骨质硬化,其机制尚不清楚。课题组前期研究发现:实验性单侧前牙反合可致小鼠TMJ出现软骨变薄、钙化增强及软骨下板状骨增厚等OA样变,软骨细胞呈现明显的成骨细胞分化表型;感受触压类力刺激的Piezo1蛋白是非神经组织细胞中最主要的力敏感蛋白,UAC刺激下表达升高;YAP是Piezo1下游重要的力转导相关分子,力刺激可促进YAP去磷酸化入核、增强其成骨细胞分化能力。OA关节软骨细胞具有软骨前体细胞的行为特征,因此我们推测:OA软骨细胞中Piezo1-YAP介导的力-生物信号转导增强,在促进OA软骨细胞向成骨细胞分化、导致OA关节骨质硬化病变中发挥重要作用。本项目拟采用Piezo1基因修饰动物、单细胞基因芯片等先进技术,论证OA软骨细胞中Piezo1-YAP这一促进软骨细胞向成骨细胞分化的力信号转导作用,为OA的治疗提供新靶点。
英文摘要
Biomechanical factor plays a critical role in osteoarthritis (OA). Abnormal dental occlusion causes temporomandibular joint (TMJ) OA. Sclerosis and degeneration are typical signs of osteoarthritic joints, but the mechanism is unclear. Recently, our previous work demonstrated that the experimental unilateral anterior crossbite (UAC) induced OA-like lesions in TMJs. The induced changes included reduction in cartilage thickness, enhancement of cartilage calcification and increasing of the subchondral plate thickness. There was also enhanced osteoblast differentiation of chondrocytes through the mechano-biological transduction. Piezo1, an activated cationic channel protein, is the most important sensitive protein which senses pressure and shear stress in cells out of nervous system. The expression of Piezo1 was upregulated under UAC stimulation. It is well documented that the transcription factor Yes-associated protein (YAP), a direct mechanotransducer and downstream of Piezo1, mediates the mechanical signals in cells. Biomechanical stimulation promotes dephosphorylation and nucleus localization of YAP in cells and enhances the osteoblast differentiation. It is well known that chondrocytes undergo osteoblast differentiation in the growth plate during development period which has characteristic of chondral-progenitor. It is then highly possible that the Piezo1-YAP pathway mediates the mechano-biological transduction in chondrocytes, and such a pathway is enhanced in OA chondrocytes, due to which the osteoblast differentiation of chondrocytes is promoted, leading to sclerosis of the OA joints. In this project, Piezo1 gene mutation mouse will be generated. Single-cell gene chip and other advanced molecular biological technologies will be adopted. The purpose is to demonstrate that the stimulated biomechanical signal transduction effect of Piezo1-YAP pathway on aberrant osteoblast differentiation of chondrocyte in OA cartilage. Completion of this project will bring about a new strategy for OA treatment.
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DOI:10.1016/j.joca.2021.05.061
发表时间:2021-08-15
期刊:OSTEOARTHRITIS AND CARTILAGE
影响因子:7
作者:Duan, J.;Zhang, J.;Wang, M.
通讯作者:Wang, M.
DOI:10.1111/odi.13914
发表时间:2021-05-30
期刊:ORAL DISEASES
影响因子:3.8
作者:Zhang, Yuejiao;Liu, Qian;Wang, Meiqing
通讯作者:Wang, Meiqing
DOI:10.1016/j.archoralbio.2022.105365
发表时间:2022-02
期刊:Archives of oral biology
影响因子:3
作者:Zhaoyichun Zhang;Lei Lu;Tao Ye;Shibin Yu;Jing Zhang;Mian Zhang;Feng He;Qian Liu;Hongxu Yang;Jianying Feng
通讯作者:Zhaoyichun Zhang;Lei Lu;Tao Ye;Shibin Yu;Jing Zhang;Mian Zhang;Feng He;Qian Liu;Hongxu Yang;Jianying Feng
DOI:10.1096/fj.202300037rr
发表时间:2023-07
期刊:The FASEB Journal
影响因子:--
作者:Peng Zhou;Hongxu Yang;Mian Zhang;Jinqiang Liu;Jia Yu;Shibin Yu;Qian Liu;YUE‐AN Zhang;Mian‐jiao Xie;Xiaojie Xu;Jiguang Liu;Mei‐qing Wang
通讯作者:Peng Zhou;Hongxu Yang;Mian Zhang;Jinqiang Liu;Jia Yu;Shibin Yu;Qian Liu;YUE‐AN Zhang;Mian‐jiao Xie;Xiaojie Xu;Jiguang Liu;Mei‐qing Wang
DOI:10.3389/fphys.2021.750468
发表时间:2021
期刊:Frontiers in physiology
影响因子:4
作者:Zhang Y;Xu X;Zhou P;Liu Q;Zhang M;Yang H;Yu S;Zhang J;Huo W;Zhao Y;Wang M
通讯作者:Wang M
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海外基金