双膦酸盐（BPs）作为治疗骨质疏松、恶性肿瘤骨转移等一线药物被广泛应用，其长期使用可引起严重的副作用- - 双膦酸盐相关颌骨骨坏死（BRONJ），但致病机制至今不明，亦无有效的针对性治疗方法。本项目组前期已成功构建了小鼠BRONJ模型，实验发现BPs诱发颌骨骨坏死比例明显较髂骨高，并通过全基因表达谱芯片分析了颌骨、髂骨BMSCs在不同BPs浓度影响下的mRNA表达谱差异，筛选出BPs影响两种来源BMSCs分化差异的关键信号通路。而不同来源的BMSCs对于BRONJ发生的影响以及治疗尚未见报道，所以本项目拟从颅颌面骨与外周骨成骨方式的差异研究BRONJ的发病机制，同时从RANKL/RANK/OPG、Wnt通路以及软骨内成骨BMPs、FGFs信号调控系统分析关键因子表达差异，采用调控Wnt、RANKL/RANK/OPG通路的药物，研究其发病的分子机制，并进一步探寻有针对性的治疗方法。

Bisphosphonate(BPs) have been used routinely to manage skeletal complications of osteoporosis, malignant tumor osseous metastasis and Paget's disease.However,a growing number of patients on long-term bisphosphonate therapy develop a devastating disease named bisphosphonate-related osteonecrosis of the jaw(BRONJ).The pathogenesis of BRONJ remains unknown. Even worth, no effective treatment is available. In previous studies,we have established a mouse model of BONJ-like disease,and showed that the morbidity of necrotic bone and impaired soft tissue healing in cranio-maxillofacial bones is obviously higher than that in periphery bones. Analysis of the difference between jaw and ilium BMSCs mRNA expression in different concentration of BPs by gene expression profile chip,and we selected two key signaling pathways.Different BMSCs influence on BRONJ occurrence and treatment has not been reported, so this project aims to investigate the pathogenesis of BRONJ on molecular level, by comparing different osteogenesis mode between periphery and cranio-maxillofacial bones; observing the key factor expression from RANKL/RANK/OPG, Wnt pathways and BMPs, FGFs signal system;as well as detecting the progression of osteonecrosis after two sources of BMSCs transplantation and administration of RANKL/RANK/OPG, Wnt signal ways drugs. Hopefully,this project will help elucidate the pathophysiology of BRONJ,ultimately develop novel approaches for prevention and treatment of human BRONJ.