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

描述(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最有文献记载的组织缺氧的例子，其中血管和骨组织的破坏是原因。在较小的范围内，应力性骨折局部破坏骨内的腔隙-管腔，从而中断气体和营养物质的运动，可能导致局限性缺氧。此外，有证据表明，骨的卸载会扰乱骨的腔隙内气体和营养物质的机械驱动运动，导致组织内的细胞缺氧。最近的活体研究表明，氧气供应的变化是骨形成的有力刺激。此外，我们有新的数据表明，硬化素，一个BMP信号的靶标，调节Wnt糖蛋白的活性，从而抑制骨形成，通过降低成骨细胞的氧分压来抑制。硬化素在维持正常骨生理方面的重要性被两种疾病状态所强调，这两种疾病都是由成骨细胞过度活跃引起的骨过度生长。低氧驱动的骨形成和低氧调节的硬化素表达背后的细胞机制尚不清楚。我们的中心假设是，低组织氧减少了硬化素的表达，这通过Wnt信号促进了骨形成。有充分的证据表明Wnt/LRP5/skerostin轴和低氧对胚胎和出生后骨骼发育的合成代谢作用，结合我们新的数据表明低氧减弱了skerostin的表达，我们假设低氧通过Wnt信号和skerostin促进骨形成的增强。我们将在两个特定的目标上测试这一假设，包括体外分子方法和新颖的体内小鼠模型系统。该项目有可能对缺氧和骨骼之间的关系产生新的见解，并确定可以通过药物操作来促进骨修复的新途径。考虑到骨科创伤构成了美国武装冲突中的大部分伤害，以及应力性骨折对军事人员的健康和战备状态的重大影响，更深入地了解缺氧、骨细胞生理和骨健康之间的关系是当务之急。 公共卫生相关性：项目叙述：随着我们完成我们的特定目标，我们将确定细胞氧气感应背后的分子机制，并阐明低氧如何调节基因表达。此外，我们还将研究低氧驱动的硬化素抑制对最终导致骨形成的信号通路(Wnt/2-catenin信号)的影响。该项目有可能为缺氧和骨骼之间的关系提供新的见解，并确定新的途径，这些途径可以通过药物手段来促进骨修复，甚至可以预防性地使用来防止骨损伤。了解氧气供应和骨细胞生理学之间的关系也将对开发有效的组织工程学策略用于骨修复具有重要意义。

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.