Inhibin Anbolism During Distraction Osteogenesis

描述(由申请人提供)：骨丢失疾病是一个主要的健康问题。尽管抗吸收药物随处可得，但仍主要需要增加患者骨形成的合成代谢药物来治疗各种临床病理。我们最近发现，抑制素A，一种通常由性腺产生的多肽激素，可以增加完整成年小鼠骨骼的骨体积和强度，并防止性腺切除引起的骨丢失。这些影响似乎是由促进骨形成的机制介导的，因为没有观察到破骨细胞数量或骨吸收的系统标志物的变化。这导致我们假设，在其他骨形成模型中，inha也是合成代谢的，例如牵张成骨(DO)，在这些模型中，inha对成骨细胞的增殖和功能的影响可能更明显。DO是一种独特的骨形成的临床方法，被认为是骨折愈合的一种变体，它将生物修复过程延伸到其自然极限。为了验证我们的假设，我们邀请了我们的同事詹姆斯·阿伦森博士的合作，他是啮齿动物模型中临床DO和基础研究DO的专家。我们认为，DO过程提供的成骨细胞形成的细胞组织和隔离使其成为了解抑制素刺激成骨作用的机制基础的唯一合适的模型。为了检验这一假设，本文提出了两个目标。目的1利用我们的InhA过表达转基因模型，我们已经证明了骨的合成代谢作用，将确定抑制素A治疗是否在牵张成骨过程中增强骨形成和僵硬。MicroCT、X光照相和组织形态计量学将用于量化InHA对骨形成反应的总的和特定于骨间隔的贡献。将进行拉伸力学测试，以确定新骨形成的硬度。目的2将确定在牵张过程中介导抑制素A促进骨形成的细胞和分子事件。我们的重点将是确定inha促进骨形成的机制是否通过增加再生组织不同区域的细胞数量和/或增加成骨细胞谱系中被招募到这一过程中的细胞的活性来实现。由此得到的数据将证明抑制素A在DO过程中的合成代谢作用，并提供对机制的洞察(S)，该机制可能是未来促进骨折愈合的合成代谢疗法开发的靶点。骨折愈合不完全或延迟是主要的健康问题，特别是在老年人口中，可用的治疗方法很少。我们最近发现，用性腺激素抑制素治疗成年小鼠可以增加骨量和强度，这表明它也可能促进骨折愈合过程中的骨形成。我们的目标是确定在一种称为肢体延长或牵张成骨的骨折愈合模型中，抑制素是否能增加新骨形成。如果抑制素可以增加肢体延长过程中产生的骨量，它也可能成为一种在骨折愈合过程中增加骨形成的治疗方法。

DESCRIPTION (provided by applicant): Diseases of bone loss are a major health issue. Despite the wide availability of anti-resorptive drugs, there is a major need for anabolic agents that increase bone formation in patients to treat a variety of clinical pathologies. We have recently shown that Inhibin A, a peptide hormone normally produced by the gonad, increases bone volume and strength in the intact adult murine skeleton, and protects against gonadectomy-induced bone loss. These effects appear to be mediated by a mechanism that increases bone formation, since no changes in osteoclast numbers or systemic markers of bone resorption are observed. This led us to hypothesize that InhA is also anabolic in other models of bone formation, such as distraction osteogenesis (DO), in which InhA effects on osteoblast proliferation and function might be more pronounced. DO is a unique clinical method of bone formation and is considered a variant of fracture healing that stretches the biological repair process to its natural limits. To test our hypothesis, we enlisted the collaboration of our colleague, Dr. James Aronson, an expert in clinical DO and basic studies of DO in rodent models. We believe the cellular organization and isolation of osteoblastogenesis offered by the DO process makes it a uniquely suitable model to gain insight into the mechanistic basis of Inhibin's stimulatory effects on bone formation. Two Aims are proposed to test the hypothesis. Aim 1 will determine if Inhibin A treatment enhances bone formation and stiffness during distraction osteogenesis, using our transgenic model of InhA overexpression in which we have demonstrated bone anabolic effects. MicroCT, radiography and histomorphometry will be used to quantify total and compartment-specific contributions of InhA to the bone formation response. Tensile mechanical testing will be performed to determine stiffness of new bone formed. Aim 2 will determine the cellular and molecular events mediating Inhibin A enhancement of bone formation during the distraction process. Our focus will be to determine if the mechanisms by which InhA increase bone formation are through increasing cell number in the different zones of regenerating tissue and/or increasing the activity of cells in the osteoblastic lineage that are recruited into the process. The resulting data will demonstrate the anabolic action of Inhibin A during DO, and provide insight into the mechanism(s) that may be targeted for future anabolic therapy development to improve fracture healing. Incomplete or delayed fracture healing is major health issue, particularly in the elderly population, and very few treatments are available. We recently showed that treatment of adult mice with the gonadal hormone Inhibin increases bone mass and strength, suggesting it might also enhance bone formation during fracture healing. Our goal is to determine if Inhibin can increase new bone formation during a model of fracture healing known as limb-lengthening or distraction osteogenesis. If Inhibin can increase the amount of bone made during limb- lengthening, it may also have potential development as a therapy for increasing bone formation during fracture healing.