内质网应激诱导的细胞凋亡在激素性骨坏死中的分子机制

Steroid-induced osteonecrosis of the femoral head is a progressive disease that generally affects patients in the third though fifth decades of life; if left untreated, it leads to complete deterioration of the hip joint. A number of different factors have been implicated in the development of osteonecrosis, but although it has been recognised for over 100 years, the biological mechanisms involved remain unclear. Previous studies have confirmed that osteocyte apoptosis is an important pathological features of steroid-induced osteonecrosis of femoral head. Therefore, recent attention has focused on the role of osteocyte apoptosis. Endoplasmic reticulum stress (ERS) pathway is a new apoptosis pathway and has been implicated in the pathogenesis of many diseases, which has led to the proposal of a new therapeutic approach targeting ER stress. But its mechanism of action in steroid-induced osteonecrosis of femoral head has not been elucidated. On the basis of primary osteoblast cells in vitro and rabbit steroid-induced osteonecrosis of the femoral head animal models in vivo, we will undertake the following studies: 1.Whether the ERS pathway is involved in steroid-induced apoptosis of primary osteoblast cells and its effects on the biological function of osteoblasts, 2 What is the difference between the ERS-induced osteoblast apoptosis pathway with classic mitochondrial apoptotic pathway and death receptor apoptotic pathway? What is the ERS-specific markers? 3 Whether inhibiting the expression of CHOP gene by RNA interferance, which is one of the key target of ERS pathway, can prevent apoptosis of osteoblast cells and delay the occurrence and development of rabbit steroid-induced osteonecrosis models? The results of this study will reveal the molecular mechanisms at the subcellular level of steroid-induced osteonecrosis of femoral head and provide new ideas and new ways for prevention and treatment of steroid-induced osteonecrosis.

激素性骨坏死发病率高、致残率高，受累人群以中青年为主，危害极大，但其发病机制尚不清楚。研究证实，骨细胞凋亡是激素性骨坏死的重要病理特征，针对骨细胞凋亡的研究将有助于揭示激素性骨坏死的分子机制。内质网应激（ERS）途径是近年发现的新的细胞凋亡途径，在多种疾病的发病机制中发挥了重要作用，但其在激素性骨坏死中的作用机制尚未阐明。本项目以原代培养成骨细胞和骨坏死动物模型为研究对象，拟开展下述研究：1.ERS途径是否参与了激素诱导的成骨细胞凋亡，其对成骨细胞的生物学功能有何影响；2.ERS诱导的成骨细胞凋亡途径与经典的线粒体和死亡受体凋亡途径有何不同与关联，能否筛查到ERS特异性标志物；3.抑制ERS途径关键靶标CHOP基因是否可以阻止成骨细胞凋亡和骨坏死的发生发展；研究结果将会揭示激素性骨坏死在亚细胞器内质网水平的分子机制，丰富与充实骨坏死的理论，为激素性骨坏死的防治提供新思路和新途径。