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: 8197727
• 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 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197727
• 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最有据可查的例子，其中血管和骨组织的破坏是其原因。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，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，骨的卸载会破坏骨的腔隙-小管空间内机械驱动的气体和营养物质的运动，导致组织内的细胞缺氧。最近的体内研究文献表明，氧气可用性的改变是骨形成的有效刺激。此外，我们有新的数据表明，硬化蛋白（BMP 信号传导的一个靶标，调节 Wnt 糖蛋白的活性，从而抑制骨形成）受到成骨细胞中氧张力降低的抑制。两种疾病状态（van Buchem 和硬化症）强调了硬化素在维持正常骨生理学中的重要性，这两种疾病状态的特征都是由过度活跃的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素表达背后的细胞机制仍不清楚。我们的中心假设是，组织氧含量低会降低硬化蛋白的表达，从而通过 Wnt 信号传导促进骨形成。提供了独立涉及Wnt/Lrp5/硬化素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的充分证据，结合我们表明缺氧减弱硬化素表达的新数据，我们假设缺氧通过Wnt信号传导和硬化素促进骨形成。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颖的体内小鼠模型系统。该项目有可能对缺氧与骨骼之间的关系产生新的见解，并确定可以通过药理学操作促进骨骼修复的新途径。考虑到骨科创伤占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，因此必须更全面地了解缺氧、骨细胞生理学和骨骼健康之间的关系。 公共健康相关性：项目叙述：当我们完成具体目标时，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，我们将检查缺氧驱动的硬化素抑制对最终导致骨形成的信号通路（Wnt/2-连环蛋白信号传导）的影响。该项目有可能对缺氧与骨骼之间的关系产生新的见解，并确定可以通过药理学方法操纵以促进骨骼修复，甚至预防性施用以防止骨骼损伤的新途径。了解氧供应和骨细胞生理学之间的关系也将对开发有效的骨修复组织工程策略产生影响。

项目成果

Modulation of osteogenic differentiation in hMSCs cells by submicron topographically-patterned ridges and grooves.

• DOI: 10.1016/j.biomaterials.2011.09.058
• 发表时间: 2012-01
• 期刊: BIOMATERIALS
• 影响因子: 14
• 作者: Watari, Shinya;Hayashi, Kei;Wood, Joshua A.;Russell, Paul;Nealey, Paul F.;Murphy, Christopher J.;Genetos, Damian C.
• 通讯作者: Genetos, Damian C.

Impaired osteoblast differentiation in annexin A2- and -A5-deficient cells.

膜联蛋白A2和-A5缺陷细胞中成骨细胞分化受损。

• DOI: 10.1371/journal.pone.0107482
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Genetos DC;Wong A;Weber TJ;Karin NJ;Yellowley CE
• 通讯作者: Yellowley CE