Inhibin Anbolism During Distraction Osteogenesis

牵张成骨过程中的抑制素代谢

• 批准号: 7484898
• 负责人: Dana Gaddy
• 金额: $ 2.5万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7484898
• 关键词: Activins; Address; Adult; Anabolic Agents; Anabolism; Androgens; Antibodies; Biological; Bone Resorption; Bone Surface; Cell Count; Cells; Clinical; Clinical Pathology; Collaborations; Data; Development; Diagnostic radiologic examination; Disease; Distal; Distraction Osteogenesis; Endocrine; Estradiol; Estrogens; Event; Follicle Stimulating Hormone; Foundations; Fracture Healing; Future; Gene Expression; Genes; Gonadal Steroid Hormones; Gonadal structure; Growth Factor; Health; Human; Immunohistochemistry; In Vitro; Inhibin A; Mechanics; Mediating; Menopause; Methods; Modeling; Molecular; Molecular Target; Mus; Natural regeneration; Numbers; Osteoblasts; Osteoclasts; Osteogenesis; Ovarian Inhibin; PCNA gene; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Process; Protein Overexpression; Publishing; Recruitment Activity; Regulation; Rodent Model; Roentgen Rays; Role; Serum; Serum Markers; Skeletal system; Skeleton; Staging; Staining method; Stains; Standards of Weights and Measures; Steroids; Stretching; Techniques; Testing; Tissues; Transgenic Model; Variant; Welts; Woman; Work; abstracting; base; bone; bone loss; bone metabolism; bone strength; bone turnover; clinically relevant; distraction; gonad function; human data; improved; in vivo; indexing; inhibin; inhibin B; insight; member; men; mouse model; peptide hormone; repaired; response; therapy development

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.

抽象的 骨质流失疾病是一个主要的健康问题。尽管抗热药物有广泛的可用性，但仍有 对于增加患者骨形成的合成代谢药物以治疗多种临床病理的主要需求。 我们最近表明，抑制素A（通常由性腺产生的肽激素）增加骨骼 完整的成年鼠骨架的体积和强度，并防止腺切除术引起的骨质流失。 这些作用似乎是由增加骨形成的机制介导的，因为 观察到骨吸收的破骨细胞数或全身标记。这导致我们假设Inha 在其他骨形成模型中也是合成代谢，例如分散骨化（DO），其中inha 对成骨细胞增殖和功能的影响可能更明显。做是一种独特的临床方法 骨形成，被认为是骨折愈合的变体，将生物修复过程扩展到其 自然限制。为了检验我们的假设，我们招募了同事James Aronson博士的合作 在啮齿动物模型中的临床DO和基础研究方面的专家。我们相信细胞组织和 DO过程提供的成骨细胞生成的隔离使其成为获得洞察力的独特模型 抑制素对骨形成的刺激作用的机械基础。提出了两个目标来测试 假设。 AIM 1将确定抑制蛋白A治疗是否增强了骨形成和刚度 分散骨气化，使用我们的inha过表达的转基因模型，我们已经证明了 骨合代作用。 MicroCT，放射线照相和组织形态法将用于量化总和 INHA对骨形成反应的特异性贡献。拉伸机械测试将是 执行以确定形成新骨的刚度。 AIM 2将确定细胞和分子事件 在干扰过程中介导抑制蛋白增强骨形成。我们的重点是 确定inha增加骨形成的机制是否通过增加细胞数量 再生组织的不同区域和/或增加成骨细胞谱系中细胞活性 招募到该过程。由此产生的数据将证明抑制蛋白A在DO期间的合成代谢作用，并且 提供有关可能针对未来合成代谢疗法开发的机制的洞察力 断裂愈合。