Hedgehog信号通路调节破骨细胞功能参与骨质疏松发生机制的研究

Osteoporosis is one of three major degenerative diseases in Orthopaedics, and its complications have been serious harm to human health and quality of life. The urgent problems facing in this field are to in-depth investigate the molecular mechanism of osteoclast abnormality in the disrupted coupling of bone resorption with bone formation and take effective and targeted therapy. Our preliminary data showed that Hedgehog signaling was involved in the starting of osteoporosis through regulating osteoclast function. However, the signal transducing cascade within osteoclast and the indirect impact on bone formation by Hedgehog signaling remain unclear. And it is also unknown whether osteoporosis could be prevented and treated through modulating Hedgehog signaling. By using conditional knockout mice, osteoporosis mouse models, in vitro culture of osteoclast and co-culture with BMSCs, our study plans to investigate the phenotype of mouse models and pathological changes in vivo, and also explore the molecular mechanism and screening the target molecules in vitro. This study will do help to develop more specific Hedgehog-related drug with light side-effect in future.

骨质疏松是骨科三大退行性疾病之一，其并发症已严重危害人类健康和生活质量。深入研究破骨成骨稳态破坏的启动因素--破骨细胞异常的分子机制，采取有效地针对性治疗，是骨质疏松防治领域亟待解决的关键问题。我们前期工作表明Hedgehog信号可能通过调节破骨细胞功能参与骨质疏松发生的启动过程。然而Hedgehog信号通路在破骨细胞内的特异应答程式、对骨形成过程的影响，以及是否能够通过调控该信号通路预防和治疗骨质疏松症尚不清楚。本研究拟采用条件性基因敲除小鼠、骨质疏松模型，体外原代诱导分化培养破骨细胞及共培养研究体系相结合的办法，体内观察小鼠表型与病理变化，体外深入研究分子机制及筛查靶目标分子，将首次明确Hedgehog信号在破骨细胞中的特异应答程式，明确Hedgehog信号下游破骨细胞特异的应答因子及对成骨调控的关键机制，对今后研发更特异，副作用更小的Hedgehog信号创新药物具有重要帮助。

骨质疏松是骨科三大退行性疾病之一，其并发症已严重危害人类健康和生活质量。深入研究破骨成骨稳态破坏的启动因素--破骨细胞异常的分子机制，采取有效地针对性治疗，是骨质疏松防治领域亟待解决的关键问题。我们前期工作表明Hedgehog信号可能通过调节破骨细胞功能参与骨质疏松发生的启动过程。然而Hedgehog信号通路在破骨细胞内的特异应答程式、对骨形成过程的影响，以及是否能够通过调控该信号通路预防和治疗骨质疏松症尚不清楚。本研究拟采用条件性基因敲除小鼠、骨质疏松模型，体外原代诱导分化培养破骨细胞及共培养研究体系相结合的办法，体内观察小鼠表型与病理变化，体外深入研究分子机制及筛查靶目标分子，将首次明确Hedgehog信号在破骨细胞中的特异应答程式，明确Hedgehog信号下游破骨细胞特异的应答因子及对成骨调控的关键机制，对今后研发更特异，副作用更小的Hedgehog信号创新药物具有重要帮助。本项目通过交配获得破骨细胞特异Ptch1及Smo敲除小鼠，明确了Hedgehog信号通路对破骨细胞成熟及功能的调节作用；并采用体外破骨细胞诱导培养，明确了Hedgehog信号在破骨细胞中的应答程式，发现TRAF6在破骨细胞中Hedgehog信号通路中的关键调控作用；进一步采用RT-PCR及细胞共培养体系，证实CTGF可能是Hedgehog信号编译后破骨细胞调控成骨的关键分子，并采用OVX小鼠验证CTGF对骨质疏松治疗的效果评价。我们的数据提示CTGF能够有效组织骨质疏松引起的骨丢失，有望成为骨质疏松治疗的新靶点。