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

缺氧对硬化素表达的调节：解释 h 的拟议机制

• 批准号: 7880273
• 负责人: DAMIAN C GENETOS
• 金额: $ 7.65万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7880273
• 关键词: Adult; Attenuated; Biological Models; Blood Vessels; Bone Density; Bone Mineral Contents; Bone Regeneration; Bone Tissue; Cell Hypoxia; Cell physiology; Cells; Conflict (Psychology); Data; Development; Disease; Embryo; Embryonic Development; Fracture; Gases; Gene Expression; Genes; Glycoproteins; Health; Hypoxia; Hypoxia Inducible Factor; In Vitro; Injury; Knowledge; Lead; Literature; Mediating; Mesenchymal; Mesenchymal Stem Cells; Military Personnel; Molecular; Movement; Mus; Nutrient; Orthopedics; Osteoblasts; Osteogenesis; Oxygen; Oxygen measurement, partial pressure, arterial; Pathway interactions; Phosphorylation; Physiology; Protein Isoforms; Readiness; Regulation; Signal Pathway; Signal Transduction; Site; Skeletal Development; Stimulus; Stress Fractures; Testing; Tissue Engineering; Tissues; Trauma; arm; bone; bone cell; bone health; deprivation; in vivo; insight; long bone; novel; novel strategies; osteoblast differentiation; osteogenic; prevent; progenitor; public health relevance; repaired; skeletal; ubiquitin ligase

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.

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实例，其中血管和骨组织的破坏是病因。在较小的范围内，应力性骨折局部破坏骨内的腔隙-小管空间，因此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，骨卸载会破坏骨腔隙-骨小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。最近在体内的研究表明，在文献中的氧可用性的改变是一个强有力的刺激骨形成。此外，我们有新的数据表明，sclerostin，BMP信号的目标，调节Wnt糖蛋白的活性，从而抑制骨形成，是通过降低成骨细胞中的氧张力抑制。两种疾病状态，货车Buchem和骨质硬化症，强调了sclerostin在维持正常骨生理学中的重要性，这两种疾病的特征都是由过度活跃的成骨细胞引起的骨过度生长。低氧驱动的骨形成与低氧调节的sclerostin表达背后的细胞机制仍然未知。我们的中心假设是，低组织氧减少sclerostin的表达，这有利于通过Wnt信号增强骨形成。提供了独立地暗示Wnt/Lrp 5/sclerostin轴和缺氧在介导胚胎和纳塔尔后骨骼发育中的合成代谢作用的充分证据，结合我们的新数据表明缺氧减弱sclerostin表达，我们假设缺氧通过Wnt信号传导和sclerostin促进增强的骨形成。我们将在两个特定的目标，包括在体外分子方法和新的体内小鼠模型系统测试这一假设。该项目有可能对缺氧和骨之间的关系产生新的见解，并确定可以操纵的新途径，以促进骨修复。考虑到骨科创伤包括美国武装冲突中的大多数损伤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，必须更深入地了解缺氧，骨细胞生理学和骨健康之间的关系。 公共卫生相关性：项目说明：当我们完成我们的具体目标，我们将确定细胞氧传感背后的分子机制，并阐明缺氧如何调节基因表达。此外，我们还将研究低氧驱动的硬化蛋白抑制对最终导致骨形成的信号通路（Wnt/2-catenin信号通路）的影响。该项目有可能对缺氧和骨之间的关系产生新的见解，并确定新的途径，可以通过人工操作来促进骨修复，甚至通过人工操作来预防骨损伤。了解氧气供应和骨细胞生理学之间的关系也将对骨修复的有效组织工程策略的发展产生影响。