激活成骨细胞低氧/HIF-1α通路促进骨形成的有益作用，正引导药用低氧模拟化合物呈热点研究内容的发展趋势。但申请者发现，继成骨细胞HIF-1α通路激活后的新生骨组织，骨塑建/骨改建过程呈现“失衡”的现象，其中与骨细胞生物学特性转化有关。本课题基于既有的研究线索，以成骨细胞/早期骨细胞、成熟期骨细胞hif-1α和pvhl基因条件敲除小鼠模型和与之相对应的细胞模型为研究对象，深入了解HIF-1α通路调控成骨细胞向骨细胞演化、骨细胞分化进程、骨细胞时空分布特征和表型表达的关键环节及其与骨改建过程间的关系；揭示激活HIF-1α通路状态下的骨细胞分别对破骨细胞、成骨细胞生成和分化的调节作用及其所涉及的细胞分子生物学事件；并且在此基础上探究此机制在雌激素缺乏导致的骨质疏松症中的角色。这不仅有助于加深或更新骨塑建/骨改建过程的认识，而且有望发现骨改建的新调控机制，为防治代谢性骨病提供新理念。

The studies have showed that hypoxia inducible factors (HIFs) and mimicking agents (HMAs) trigger the initiation and promotion of angiogenic-osteogenic cascade events. Such discoveries suggest promising approaches for the development of novel therapies to improve bone regeneration and formation procedures. However, we recently found that activation of HIF1α in osteoblasts through disruption of its degradation pathway leadings to an imbalance in the bone remodeling process associated with osteocyte differentiation obstacle. Based on this clue, in this proposal, we will investigate the regulatory roles of HIF-1α pathway on late osteoblasts differentiating into osteocytes and differentiation of osteocytes, as well as relevance to bone remodeling processes, employing the conditional knockout mouse models that hif-1α or pvhl gene in osteoblast/early osteocyte and osteocyte were deleted, respectively. We will reveal the cellular and molecular mechanisms of hypoxia/HIF-1a pathway in regulating osteocyte survival, fate, dendrite/canaliculi formation and phenotype expression. And we will further clarify the essential function of osteocyte biological behavior in Estrogen deficient induced osteoporosis. We expect that the proposed studies will deepen the understanding of the mechanism of bone remodeling, provide important new therapy targets to improve bone reconstruction, exploit novel approaches for patients with difficulty bone diseases.