骨性关节炎（OA）是肌肉骨骼系统最常见的疾病，但其发病机制尚未明确，多认为与关节软骨细胞（ACCs）及软骨下成骨细胞（SBOs）相互作用有关，课题组近期研究发现OA进程中ACCs与SBOs相互作用是通过MAPK-ERK1/2信号通路介导，而ERK1/2磷酸化上调有助于软骨退变及软骨下骨硬化。在进一步证实ERK1/2抑制剂可在体外细胞共培养模型中逆转由此引发的骨与软骨细胞表型改变的基础上，本课题拟在体外模拟膝关节生物力学环境复制软骨与软骨下骨相互作用模型，以ERK1/2为切入点研究ERK1/2抑制剂在体外OA细胞模型及体内动物模型中对ACCs及SBOs表型变化的影响，进一步阐述ERK1/2在OA发病中的作用。本课题将证实我们提出的"ERK1/2抑制剂→ERK1/2磷酸化↓→RUNX2表达↓→逆转OA表型→抑制ACCs肥大、降解及软骨下骨硬化→阻止OA进程"假说，为OA防治提供新思路及新靶点。

Osteoarthritis (OA) is the most common form of musculo-skeletal disorders but the exact aetiology is largely unknown.most of the studies indicated that a potential interaction of articular chondrocytes (ACCs) and subchondral bone osteoblasts (SBOs) in OA microenvironment may lead to OA progression.Our study group found that in OA SBOs can directly or indirefctly affect hypertrophic marker gene expression and cartilage degeneration.The interaction between ACCs and SBOs during OA progression is mediated via the Mitogen-Activation Protein Kinases (MAPK)-Extracellular Signal-Regulated Kinases 1 and 2(ERK1/2), and that altered ERK1/2 phosphorylation contributes to cartilage degeneration and subchondral bone changes.Our study will model the knee joint Biomechanics environment in vitro and the interaction between cartilage and the underlying subchondral bone in OA.We target to test the potential efficacy of a selective ERK1/2 inhibitor in the OA animal model via addining the ERK1/2 specific inhibitor and analyze cartilage hypertrophy and subchondral bone osteosclerosis relevant markers.Eventually we will investigate the mechanism which ERK1/2 and the ERK1/2 specific inhibitor affect the interaction between ACCs and SBOs in animal models, furthermore,to determine whether the ERK signaling pathway is responsible for the OA pathological changes.Our purpose is to prove the hypothesis- - ERK1/2 specific inhibitor→ERK1/2 phosphorylation↓→RUNX2 expression↓→reversal of osteoarthritis phenotypic changes→to restrain cartilage hypertrophy and degredation and the subchondral bone osteosclerosis→slowing OA progression.Therefore,for applying informations to the development of scientific basis and therapeutic interventions of OA.

骨性关节炎（OA）是肌肉骨骼系统最常见的疾病，但其发病机制尚未明确，多认为与关节软骨细胞（ACCs）及软骨下成骨细胞（SBOs）相互作用有关，课题组近期研究发现OA进程中ACCs与SBOs相互作用是通过MAPK-ERK1/2信号通路介导，而ERK1/2磷酸化上调有助于软骨退变及软骨下骨硬化。在进一步证实ERK1/2抑制剂可在体外细胞共培养模型中逆转由此引发的骨与软骨细胞表型改变的基础上，本课题以ERK1/2为切入点研究ERK1/2抑制剂在体外OA细胞模型及体内动物模型中对ACCs及SBOs表型变化的影响，进一步阐述ERK1/2在OA发病中的作用。证实我们提出的“ERK1/2抑制剂→RUNX2表达↓→逆转OA表型→抑制ACCs肥大、降解及软骨下骨硬化→阻止OA进程”假说，为OA防治提供新思路及新靶点。同时，本课题组在此基础上，进一步验证高脂血症通过MAPK-ERK1/2通路影响ACC线粒体形态与功能，增大其氧化应激压力，从而造成ACC肥大及降解，为OA的全身性防治提供的新的策略，为广大OA患者提高预后作出贡献。