Regulation of sclerostin expression by hypoxia: A proposed mechanism to explain h

描述（由申请人提供）：骨组织缺氧通常是骨骼创伤的结果。骨折部位的局部缺氧可能是组织缺氧的最佳记录，其中血管和骨组织的破坏是导致的。在较小的范围内，应力性骨折局部破坏骨腔管空间，从而中断气体和营养物质的运动，可能导致局部缺氧。此外，有证据表明，骨的卸载会破坏骨腔管间隙内气体和营养物质的机械驱动运动，导致组织内细胞缺氧。最近文献中的体内研究表明，氧可用性的改变是骨形成的有力刺激。此外，我们有新的数据表明，硬化蛋白，BMP信号的靶标，调节Wnt糖蛋白的活性，从而抑制骨形成，被抑制在成骨细胞中的氧张力降低。两种疾病状态（van Buchem和sclerosteosis）强调了硬化蛋白在维持正常骨生理方面的重要性，这两种疾病都以成骨细胞过度活跃引起的骨过度生长为特征。缺氧驱动的骨形成与缺氧调节的硬化蛋白表达背后的细胞机制尚不清楚。我们的中心假设是低组织氧降低了硬化蛋白的表达，从而通过Wnt信号促进骨形成。提供了充分的证据，独立暗示Wnt/Lrp5/sclerostin轴和缺氧在介导胚胎和出生后骨骼发育中的合成代谢作用，结合我们的新数据表明缺氧会减弱硬化蛋白的表达，我们假设缺氧通过Wnt信号和硬化蛋白促进骨形成。我们将在两个具体目标中测试这一假设，包括体外分子方法和新的体内小鼠模型系统。该项目有可能对缺氧与骨之间的关系产生新的见解，并确定可以通过药理学操纵促进骨修复的新途径。考虑到美国武装冲突中骨科创伤占大部分，以及应力性骨折对军事人员健康和战备状态的重大影响，更深入地了解缺氧、骨细胞生理和骨骼健康之间的关系势在必行。

DESCRIPTION (provided by applicant): Bone tissue hypoxia generally occurs as a consequence of skeletal trauma. Regional hypoxia at a fracture site is probably the best-documented example of tissue hypoxia, wherein disruption of blood vessels and bone tissue are causative. On a smaller scale, stress fractures that locally disrupt the lacunar-canalicular space within bone, and, therefore, interrupt the movement of gases and nutrients could cause localized hypoxia. In addition, there is evidence to suggest that unloading of bone, which would disrupt mechanically driven movement of gases and nutrients within the lacunar-canalicular space of bone, leads to cellular hypoxia within the tissue. Recent in vivo studies in the literature suggest that alterations in oxygen availability are a potent stimulus for bone formation. In addition, we have novel data demonstrating that sclerostin, a target of BMP signaling that regulates the activity of Wnt glycoproteins and therefore inhibits bone formation, is suppressed by a reduction in oxygen tension in osteoblastic cells. The importance of sclerostin in maintaining normal bone physiology is underscored by two disease states, van Buchem and sclerosteosis, which are both characterized by bone overgrowth caused by hyperactive osteoblasts. The cellular mechanisms behind hypoxia-driven bone formation versus hypoxia-regulated sclerostin expression remain unknown. Our central hypothesis is that low tissue oxygen decreases sclerostin expression, which facilitates enhanced bone formation through Wnt signaling. Provided the ample evidence that independently implicates the Wnt/Lrp5/sclerostin axis and the anabolic effect of hypoxia in mediating both embryonic and post- natal skeletal development, combined with our novel data indicating that hypoxia attenuates sclerostin expression, we hypothesize that hypoxia facilitates enhanced bone formation through Wnt signaling and sclerostin. We will test this hypothesis in two Specific Aims encompassing in vitro molecular approaches and novel in vivo murine model systems. This project has the potential to yield new insight into the relationship between hypoxia and bone and identify novel pathways that could be manipulated pharmacologically to promote bone repair. Considering that orthopaedic trauma comprises the majority of injuries in US armed conflicts and the significant impact of stress fracture on the health and operational readiness of military personnel, a more thorough understanding of the relationship between hypoxia, bone cell physiology and bone health is imperative. PUBLIC HEALTH RELEVANCE: Project narrative: As we complete our specific aims we will identify the molecular mechanisms behind cellular oxygen sensing and elucidate how hypoxia regulates gene expression. In addition, we will examine the ramifications of hypoxia-driven Sclerostin suppression, on signaling pathways (Wnt/2-catenin signaling) that ultimately lead to bone formation. This project has the potential to yield new insight into the relationship between hypoxia and bone and identify novel pathways that could be manipulated pharmacologically to promote bone repair or even administered prophylactically to prevent bone damage. Understanding the relationship between oxygen supply and bone cell physiology will also have ramifications for the development of effective tissue engineering strategies for bone repair.