活性维生素D缺乏导致颞下颌关节骨关节病的作用机制研究

颞下颌关节骨关节病（TMJ-OA）为临床常见疾病，但其发病机制尚不明确。我们的前期研究发现活性维生素D缺乏可导致TMJ-OA，且髁状突软骨细胞内DNA损伤及衰老相关指标p53表达水平明显增高。为了进一步明确其发病机制，本研究拟采用基因沉默的方法于体外构建维生素D受体缺乏的TMJ-OA软骨细胞模型，予以活性维生素D、p53抑制剂进行干预，检测氧化应激及衰老相关指标。同时，给予活性维生素D缺乏的1α(OH)ase-/-小鼠抗氧化剂喂养，或构建1α(OH)ase-/-p53-/-双基因突变小鼠，将其与同窝野生型小鼠比较，观察颞下颌关节的表型差异。本研究结果将从细胞及动物水平明确活性维生素D缺乏导致氧化应激水平增高，激活p53-p21信号通路，加速细胞衰老，进而导致TMJ-OA的作用机制，并为其临床应用于治疗TMJ-OA提供理论和实验依据。

Temporomandibular joint osteoarthritis (TMJ-OA) is a common disease, however, its pathogenesis is still unclear. Our previous study found that 1alpha, 25dihydroxylvitaminD [1,25(OH)2D] deficiency can lead to TMJ-OA, and the expressions of DNA damage and aging-related indicators were higher. To clarify the possible mechanism, we plan to use gene silencing method to harvest 1,25(OH)2D deficiency condylar chondrocytes in vitro, give exogenous oxidative stimuli, and then the 1,25(OH)2D and p53 inhibitor, detecting the level of oxidative stress, cell senescence and osteoarthritis-related indicators. To investigate the further antioxidate effect of 1,25(OH)2D on TMJ, 1α(OH)ase-/- mice will be maintained on a diet of rescue diet with N-acetyl-L-cysteine (NAC) solution, or subcutaneous injection of 1,25(OH)2D, and their wild-type littermates will be fed on a diet of regular mouse chow. The mice will be sacrificed at 6-month-old, and the results will be analyzed by imageology, histomorphology immunohistochemistry and biochemical detection. At last, to investigate the role of p53 in the TMJ-OA induced by 1,25(OH)2D deficiency, we will delete p53 gene in 1α(OH)ase-/- mice, their phenotypes will be compared in TMJ with those of p53 deficient, 1α(OH)ase-/- and wild-type mice. Results from this study will be helpful to elucidate the mechanism of 1,25(OH)2D deficiency-induced TMJ-OA, and will provide theoretical and experimental basis for the applications of 1,25(OH)2D in clinical study on treatment of TMJ-OA.