Inhibin Anbolism During Distraction Osteogenesis

牵张成骨过程中的抑制素代谢

• 批准号: 7449520
• 负责人: Dana Gaddy
• 金额: $ 17.76万
• 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 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7449520
• 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; Elderly; Endocrine; Estradiol; Estrogens; Event; Follicle Stimulating Hormone; Foundations; Fracture Healing; Future; Gene Expression; Genes; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Gonadal structure; Growth Factor; Health; Human; Immunohistochemistry; In Vitro; Inhibin A; Limb structure; 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; Population; 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; 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

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.

描述（由申请人提供）：骨质流失疾病是一个主要的健康问题。尽管抗抑郁药的可用性广泛，但对于增加患者的骨形成以治疗各种临床病理的骨骼形成的主要需求。我们最近表明，通常由性腺产生的肽激素A抑制素A增加了完整的成年鼠骨架中的骨体积和强度，并防止了性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，因为未观察到破骨细胞数量或骨吸收的全身标志物的变化。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为明显。 DO是骨形成的独特临床方法，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，我们招募了同事詹姆斯·阿隆森（James Aronson）博士的合作，詹姆斯·阿农森（James Aronson）是临床DO和对啮齿动物模型中DO的基础研究的专家。我们认为，DO过程提供的细胞组织和隔离成骨母细胞生成使其成为一个独特的模型，可以深入了解抑制素对骨形成的刺激作用的机械基础。提出了两个目的来检验假设。 AIM 1将使用我们的INHA过表达的转基因模型来确定抑制蛋白A治疗是否会增强分散成骨的过程中的骨形成和僵硬，在这种模型中我们证明了骨合成代谢作用。 MicroCT，放射线照相和组织形态计量法将用于量化INHA对骨形成反应的总和特异性贡献。将进行拉伸机械测试，以确定形成新骨的刚度。 AIM 2将确定介导抑制素在分散过程中骨骼形成的增强的细胞和分子事件。我们的重点是确定inha增加骨形成的机制是否是通过增加再生组织的不同区域的细胞数量和/或增加募集成骨细胞谱系中细胞活性的机制。最终的数据将证明DO期间抑制素A的合成代谢作用，并洞悉可能针对未来合成代谢疗法开发以改善骨折愈合的机制。不完整或延迟的骨折愈合是主要的健康问题，尤其是在老年人群中，很少有治疗方法。我们最近表明，用性腺激素抑制素治疗成年小鼠会增加骨骼质量和强度，这表明它在裂缝愈合过程中也可能增强骨形成。我们的目标是确定抑制剂在被称为肢体延长或分散骨质发生的断裂愈合模型中是否会增加新的骨形成。如果抑制素可以增加肢体延长期间骨骼的量，则它也可能具有潜在的发育，作为在裂缝愈合过程中增加骨形成的疗法。