Inhibin Anbolism During Distraction Osteogenesis

摘要 骨质疏松症是一个主要的健康问题。尽管抗吸收药物的广泛可用性， 主要需要增加患者骨形成的合成代谢剂以治疗各种临床病理。 我们最近发现抑制素A，一种通常由性腺产生的肽激素， 体积和强度在完整的成年小鼠骨骼，并防止性腺切除术引起的骨丢失。 这些作用似乎是由增加骨形成的机制介导的，因为在骨形成过程中， 观察破骨细胞数目或骨吸收的全身标记物。这使我们假设InhA 在其他骨形成模型中也是合成代谢的，例如牵张成骨（DO），其中InhA 对成骨细胞增殖和功能的影响可能更显著。DO是一种独特的临床方法， 骨形成，被认为是骨折愈合的一种变体，其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， 临床DO和啮齿动物模型DO基础研究专家。我们相信细胞组织和 DO过程提供的成骨细胞生成的分离使其成为一种独特的合适模型， 抑制素对骨形成的刺激作用的机制基础。提出了两个目标来测试 假说.目的1将确定抑制素A治疗是否在治疗期间增强骨形成和刚度。 牵张成骨，使用我们的InhA过表达的转基因模型，我们已经证明， 骨合成作用。将使用MicroCT、X射线照相术和组织形态计量学来量化总的和 InhA对骨形成反应的区室特异性贡献。拉伸机械测试将 以确定形成的新骨的刚度。目标2将确定细胞和分子事件 在牵张过程中介导抑制素A增强骨形成。我们的重点将是 确定InhA增加骨形成的机制是否是通过增加骨组织中的细胞数量， 再生组织的不同区域和/或增加成骨细胞谱系中的细胞的活性， 招募到这个过程中。所得数据将证明抑制素A在DO期间的合成代谢作用， 提供对可能成为未来合成代谢治疗开发目标的机制的深入了解，以改善 骨折愈合

ABSTRACT 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.