Role of estrogen receptor signaling in low-magnitude high-frequency vibration-induced effects on bone fracture healing

雌激素受体信号在低强度高频振动诱导的骨折愈合效应中的作用

• 批准号: 413253470
• 负责人: Privatdozentin Dr. Melanie Haffner-Luntzer
• 金额: --
• 依托单位: Institut für Unfallchirurgische Forschung und Biomechanik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/413253470?language=en
• 关键词: Role; estrogen; receptor; signaling; low

Due to its osteoanabolic effects, low-magnitude high-frequency whole-body vibration (LMHFV) is supposed to provide a non-invasive, cost-effective and safe treatment to increase bone mass and improve bone quality in osteoporotic patients. Much less is known about the effects of LMHFV on bone fracture healing. Experimental studies reported contradictory results. It has been shown that LMHFV supports bone regeneration in estrogen-deficient rodents, whereas, in estrogen-competent animals, no or negative effects were observed. This indicates a major role for estrogen in mechanostimulation of bone repair and implies that LMHFV might only be beneficial in confined target populations. However, the underlying molecular mechanisms remain poorly understood. In preliminary work for this proposal, we studied the role of estrogen receptor (ER) signaling in LMHFV-induced effects on fracture healing using ER alpha- and ER beta-knockout mice. Our results suggest a critical role of ER alpha-, but not of ER beta-signaling. However, remaining open questions which should be addressed by the proposed project are, if ligand-dependent or ligand-independent ER alpha-signaling is responsible for the effects of LMHFV and which cell types in the fracture callus are the targets for mechanostimulation. To answer the first question, we will use ER alpha-AF1-0 and ER alpha-AF2-0 mice for fracture healing studies, since the AF-1 domain is responsible for ligand-dependent and -independent signaling, whereas AF-2 exerts only ligand-dependent signaling. To identify the involved cell types, we will use cell-specific ER alpha-knockout mice. Additional in vivo and in vitro experiments will be performed to identify molecular targets of ER alpha signaling during LMHFV and if ER alpha- signaling interact with other pathways, such as Wnt/beta-catenin-signaling, during mechanotransduction. The results of the proposed project might be clinically relevant to establish LMHFV-based treatment options for fracture patients.

由于其骨合成代谢作用，低幅度高频全身振动（LMHFV）被认为是一种非侵入性，成本效益和安全的治疗方法，以增加骨量和改善骨质疏松症患者的骨质量。关于LMHFV对骨折愈合的影响知之甚少。实验研究报告了相互矛盾的结果。已经表明，LMHFV支持雌激素缺乏的啮齿动物的骨再生，而在雌激素活性动物中，没有观察到或观察到负面影响。这表明雌激素在骨修复的机械刺激中起主要作用，并意味着LMHFV可能仅在有限的目标人群中有益。然而，潜在的分子机制仍然知之甚少。在这项建议的初步工作中，我们研究了雌激素受体（ER）信号转导的作用，LMHFV诱导的影响骨折愈合使用ER α和ER β基因敲除小鼠。我们的研究结果表明，ER α信号的关键作用，但不是ER β信号。然而，剩余的开放问题，这应该解决的拟议项目是，如果配体依赖性或配体非依赖性ER α信号是负责LMHFV的影响，以及骨折骨痂中的细胞类型是机械刺激的目标。为了回答第一个问题，我们将使用ER α-AF 1 -0和ER α-AF 2 -0小鼠进行骨折愈合研究，因为AF-1结构域负责配体依赖性和非依赖性信号传导，而AF-2仅发挥配体依赖性信号传导。为了鉴定所涉及的细胞类型，我们将使用细胞特异性ER α敲除小鼠。将进行额外的体内和体外实验以鉴定LMHFV期间ER α信号传导的分子靶点，以及ER α信号传导是否与机械转导期间的其他途径（如Wnt/β-连环蛋白信号传导）相互作用。拟议项目的结果可能与临床相关，以建立基于LMHFV的骨折患者治疗方案。