HIF-1α通过负向调控FAM20C维持骨细胞矿化功能稳态在老年性骨质疏松症中的作用机制研究

骨细胞主导骨基质矿化过程，过度矿化将增加骨脆性并引发骨质疏松症，而其中机制尚不明确。我们前期发现，骨组织中HIF-1α表达随增龄而降低；在沉默HIF-1α的骨细胞中，芯片筛选出FAM20C表达上调，其作为蛋白激酶可催化DMP-1，引起骨矿化过量；同时证实，该现象与FAM20C启动子区低甲基化有关。由此推测：HIF-1α可能通过负向调控FAM20C介导的DMP-1表达维持骨细胞矿化功能稳态。本课题拟以骨细胞Hif-1α条件性基因敲除/激活小鼠和老年小鼠，以及相对应的细胞模型为主要研究对象，通过系列体内/体外实验，明确骨细胞中HIF-1α、FAM20C、DMP-1的增龄性表达规律及其相关性，重点阐释HIF-1α负向调控FAM20C及其进一步调节DMP-1的分子机制，并探索该途径在治疗老年骨质疏松上的可能性。本课题以骨细胞矿化为关键调控环节，有望为维持骨健康、防治老年性骨质疏松症提供新举措。

Osteocytes dominate the process of bone matrix mineralization. Excessive mineralization will cause increased bone fragility and osteoporosis, the regulatory mechanism, however, is still unclear. Previously, we found that the expression of HIF-1α decreased in bone tissues with ageing. When silencing HIF-1α in osteocytes, we found the up-regulated FAM20C gene through chip screening, which acts as a protein kinase to catalyze DMP-1 and cause increased bone mineralization. It was further found that this phenomenon was related to low-level methylation of the FAM20C promoter region. Therefore, it is speculated that HIF-1α may maintain the homeostasis of osteocytic mineralization through negative regulation of FAM20C-mediated DMP-1 expression. This project intends to use Hif-1α osteocyte-conditional knockout/activation mice and aged mice as the main research models, as well as the corresponding cell model. Through a series of in vivo/in vitro experiments, it is planned to clarify the age-related expression characteristics and correlation of HIF-1α, FAM20C, and DMP-1 in osteocytes. Further, the project focuses on explaining the molecular mechanism of HIF-1α negatively regulating FAM20C and further regulating DMP-1, and exploring the possibility of this approach in the treatment of senile osteoporosis. This subject takes osteocytic mineralization as the key control link, which is expected to provide new measures for maintaining bone health, preventing and treating senile osteoporosis.