咬合力是天然生物力，上下牙接触关系异常可致咬合力异常。课题组最新研究发现，单侧前牙反合（UAC）可致下颌髁突深层软骨细胞超微结构损伤、钙化软骨带增厚，软骨细胞异常分化、软骨变薄。钙内流是细胞受力刺激后的初始反应之一，可激活CaMKⅡ-Ihh信号促软骨细胞分化，同时激活PTHrP-PPR信号负反馈调节Ihh的分泌。本项目拟对Ihh受体Smo基因敲除鼠、PTHrP受体Ppr基因敲除鼠及Ppr过表达鼠施以UAC刺激，从影像学、组织学、分子生物学等方面，评价颞颌关节变化，结合离体加载实验和局部注射相应药物的在体实验，论证：深层软骨细胞超微结构损伤相关的软骨钙化及CaMKⅡ-Ihh和PTHrP-PPR信号失衡所致软骨细胞过度分化，是UAC导致OA的重要细胞与分子病理机理；钙化软骨带向软骨浅层推进程度可作为OA软骨退变的诊断和评价指标；改善生物力环境、阻断软骨细胞异常分化是治疗颞颌关节OA的主要策略。

Occlusal loading is a natural biomechanical stimulation to the temporomandibular joints (TMJs). Changes in occlusion contact relation will lead to a loading alteration of TMJs. In recent, we developed a unilateral anterior crossbite (UAC) relation which can induce ultrastructural lesions of the hypertrophic chondrocytes and also calcium deposition in matrix which increased the thickness of the calcific cartilage zone of the mandibular condylar cartilage. There was also enhanced chondrocytes differentiation activity so that the hypertrophic and prehypertrophic zones grew thinning. Many reports stated that calcium influx is one of the early responses of the chondrocytes to the mechanical stimulation which immediately activates CaMKⅡ-Ihh signaling to stimulate chondrocytes differentiation, and upregulates PTHrP-PPR signaling to negatively modulate Ihh. In the present project, we will deliver UAC stimulation to the Tamoxifen inducible cartilage-specific Smo knockout mouse, the Tamoxifen inducible cartilage-specific Ppr knockout mouse and constitutively active Ppr transgenic mouse. The changes in TMJs will be investigated with the methods of Micro-CT, histology, and molecular biology. We will also conduct in vitro experiments via Flexcell loading on the isolated chondrocytes and in vivo experiments by injecting relative inhibitors or activators to TMJ region. The aim of this project is to verify that the calcification directed ultrastructural lesions of the hypertrophic chondrocytes in the deep zone of the articular cartilage and the aberrant chondrocyte differentiate due to the unbalanced CaMKⅡ-Ihh and PTHrP-PPR signalings are the principle cellular and molecular mechanisms of the UAC induced TMJ OA. The superficial invasion of the calcific cartilage zone is expected to be diagnostic and evaluative for OA progress. Elimination of the abnormal biomechanical stimulation and blocking the aberrant chondrocyte differentiation will be the principle therapeutic strategy of TMJ OA.