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: 8046399
• 负责人: DAMIAN C GENETOS
• 金额: $ 7.36万
• 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/8046399
• 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）：骨骼组织缺氧通常是由于骨骼创伤而发生的。骨折部位的区域缺氧可能是组织缺氧的最佳记录例子，其中血管和骨组织的破坏是病因。在较小的规模上，局部破坏骨内的lacunar骨空间的应力骨折，因此中断气体和养分的运动可能会导致局部缺氧。此外，有证据表明，骨骼的卸载会破坏骨骼空间内机械驱动的气体和养分的运动，从而导致组织内的细胞缺氧。文献中最近的体内研究表明，氧气可用性的改变是骨形成的有效刺激。此外，我们还具有新的数据，表明硬化素是调节Wnt糖蛋白活性并因此抑制骨形成的BMP信号的靶标，它通过成骨细胞中的氧张力的降低而抑制了骨形成。硬化蛋白在维持正常骨生理学方面的重要性是由两个疾病状态（van Buchem和硬化症）强调的，它们的特征在于由多活跃成骨细胞引起的骨过度生长。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，这促进了通过Wnt信号传导增强的骨形成。提供了充分的证据，表明独立含义Wnt/LRP5/硬化蛋白轴以及缺氧在介导胚胎和后骨骼后发育中缺氧的合成代谢作用，加上我们的新型数据，表明缺氧减弱了硬化蛋白的表达，我们假设低氧可以通过WES骨骼形成，从而增强了骨骼的形成和Scer蛋白。我们将在包括体外分子方法和新型体内鼠模型系统的两个特定目的中检验这一假设。该项目有可能对缺氧和骨骼之间的关系产生新的见解，并确定可以在药理上操纵以促进骨骼修复的新型途径。考虑到整形外科创伤包括美国武装冲突中的大部分伤害以及压力骨折对军事人员健康和操作准备的重大影响，因此对缺氧，骨细胞生理和骨骼健康之间的关系有了更透彻的了解。 公共卫生相关性：项目叙述：当我们完成特定目标时，我们将确定细胞氧感测背后的分子机制，并阐明缺氧如何调节基因表达。此外，我们将在信号通路（Wnt/2-catenin信号传导）上检查低氧驱动的硬化抑制抑制的后果，最终导致骨形成。该项目有可能对缺氧和骨骼之间的关系产生新的见解，并确定可以在药理上操纵的新途径，以促进骨修复，甚至预防性地施用以防止骨骼损伤。了解氧气供应与骨细胞生理学之间的关系也将产生有效的组织工程策略的后果，以进行骨骼修复。