ACTIVIN, INHIBIN AND FOLLISTATIN AND OSTEOBLASTOGENESIS

激活素、抑制素、卵泡抑素和成骨细胞生成

• 批准号: 6150641
• 负责人: Dana Gaddy
• 金额: $ 22.43万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-15 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6150641
• 关键词: SDS polyacrylamide gel electrophoresis; athymic mouse; autoradiography; bone marrow; cell growth regulation; densitometry; enzyme linked immunosorbent assay; follistatin; hormone regulation /control mechanism; immunocytochemistry; immunoprecipitation; inhibin; laboratory mouse; mixed tissue /cell culture; molecular cloning; osteoblasts; osteoclasts; osteogenesis; physiologic bone resorption; protein kinase; radioimmunoassay; receptor expression; western blottings

Activins (ACTs) are growth factors in the TGFbeta superfamily whose effects are antagonized by inhibin (INH) and follistatin (FS) through different mechanisms. Although these components comprise a complex interactive regulatory loop in the anterior pituitary to exert endocrine, paracrine, and autocrine regulation of follicle stimulating hormone (FSH) production, the contribution of these molecules to bone remodeling has not been previously addressed. Preliminary results leading to this application demonstrate that INH suppression of osteoblastogenesis in ex vivo marrow cultures is also associated with the inhibition of osteoclastogenesis. ACT, on the other hand, promotes both osteoclastogenesis and osteoblastogenesis. Results also show a differential effect of inhibin and follistatin on osteoblastogenesis and osteoclastogenesis: INH acts on early osteoblast progenitors to prevent their commitment to pre-osteoblasts capable of expressing alkaline phosphatase (AP). INH suppression of osteoblastogenesis is associated with decreased osteoclastogenesis. Significantly, the maintenance of the early INH effect in the presence of exogenous ACT is demonstration of uniquely INH-specific effect which is unopposed by ACT, and is a likely mediated by INH-specific binding sites. FS prevents the full differentiation of committed pre-osteoblasts expressing AP to osteoblasts producing mineralized matrix, but does not suppress osteoclast development in primary bone marrow cultures. These in vitro effects are completely consistent with the presence of ovarian inhibin in the circulation (and thus accessible to bone marrow) serving to limit ACT-stimulated bone turnover in intact mice and in cycling women. Thus, the current studies will test the hypotheses that an integrated loop, similar to that regulating pituitary FSH, exists within the bone marrow to regulate bone remodeling, whereby the stimulatory effect of locally produced ACT is modulated by endocrine-derived INH and bone marrow- derived FS. Loss of gonadal INH by gonadectomy should increase tonic ACT action in the marrow, resulting in increased bone turnover. To test these hypotheses, experiments will define the temporal expression of and sensitivity to ACT, INH, and FS which lead to stage-specific effects on bone marrow osteoblastogenesis and osteoclastogenesis; determine the extent to which these effects are targeted directly toward cells of the osteoblast lineage; and determine the physiological relevance of these agents on bone turnover in vivo. The definition of the combined and respective contributions of these hormones during mouse osteoblastogenesis will provide insight into their potentially similar roles in cycling and post-menopausal women.

激活素（ACT）是TGF β超家族中的生长因子， 这种作用可被INH和FS拮抗， 不同的机制。 虽然这些组件构成了一个复杂的 垂体前叶中的交互式调节回路 卵泡刺激的内分泌、旁分泌和自分泌调节 激素（FSH）的产生，这些分子对骨的贡献 以前没有提到过重塑。 初步结果 导致该应用证明INH抑制 离体骨髓培养中的成骨细胞生成也与 破骨细胞生成的抑制。 另一方面， 破骨细胞生成和成骨细胞生成。结果还显示， 卵泡抑素和卵泡抑素对成骨细胞生成的不同作用， 破骨细胞生成：INH作用于早期成骨细胞祖细胞， 他们致力于前成骨细胞能够表达碱性 磷酸酶（AP）。 INH对成骨细胞生成的抑制与 破骨细胞生成减少 值得注意的是， 在外源性ACT存在下，INH的早期效应被证实 具有独特的INH特异性作用，不受ACT的反对， 可能由INH特异性结合位点介导。FS可防止完全 表达AP的定向前成骨细胞分化为 成骨细胞产生矿化基质，但不抑制 破骨细胞在原代骨髓培养物中的发育。 这些体外 这些效应与卵巢中存在的促性腺激素完全一致 在血液循环中（因此可以进入骨髓）， ACT刺激完整小鼠和骑自行车女性的骨转换。 因此，在本发明中， 当前的研究将测试这样的假设：集成回路， 类似于调节垂体FSH，存在于骨髓中 调节骨重建，从而发挥局部的刺激作用 产生的ACT受内分泌源性INH和骨髓调节， 导出FS。 性腺切除术导致的性腺INH丢失应增加 ACT作用于骨髓，导致骨转换增加。 测试 这些假设，实验将定义的时间表达， 对ACT、INH和FS的敏感性，导致阶段特异性效应， 骨髓成骨细胞生成和破骨细胞生成;确定 这些作用直接针对组织细胞的程度 成骨细胞谱系;并确定这些生理相关性 药物对体内骨转换的影响 组合的定义和 这些激素在小鼠 成骨细胞生成将提供对它们潜在相似的 在骑自行车和绝经后妇女中的作用。