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: 6350702
• 负责人: Dana Gaddy
• 金额: $ 24.03万
• 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/6350702
• 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（ACTS）是TGFBETA超家族中的生长因子 通过抑制素（INH）和Follistatin（FS）拮抗作用。 不同的机制。 尽管这些组件包括一个复杂的 前垂体中的互动调节环施加 毛囊的内分泌，旁分泌和自分泌调节刺激 激素（FSH）产生，这些分子对骨的贡献 以前尚未解决重塑。 初步结果 导致此应用表明INH抑制 离体骨髓培养物中的成骨细胞生成也与 破骨细胞生成的抑制作用。 另一方面，行动促进 整骨构成和成骨细胞生成。结果还显示 抑制素和卵脂素对成骨细胞生成的差异作用以及 破骨细胞生成：INH作用于早期成骨细胞祖细胞以防止 他们对能够表达碱性碱性细胞的承诺 磷酸酶（AP）。 INH抑制成骨细胞生成是相关的 破骨细胞生成降低。 值得注意的是，维护 在存在外源性的情况下的早期INH效应是示范 具有独特的INH特异性效应，该作用不受ACT的反对，是一个 可能是由INH特异性结合位点介导的。 FS防止完整 差异化表达AP的固定前细胞的差异 成骨细胞产生矿化基质，但不抑制 原代骨髓培养物中的破骨细胞发育。 这些在体外 作用与卵巢抑制剂的存在完全一致 在循环中（因此可以使用骨髓），以限制 在完整的小鼠和骑自行车的妇女中，作用刺激了骨转换。 因此， 当前的研究将检验综合循环的假设， 与调节垂体FSH的调节相似，存在于骨髓内 调节骨骼重塑，从而局部刺激作用 生产的行为受内分泌衍生的INH和骨髓调节 - 派生的FS。 促性腺切除术失去性腺INH应增加补品 在骨髓中采取行动，导致骨转换增加。 测试 这些假设，实验将定义和 对行动，INH和FS的敏感性，导致对阶段的影响 骨髓成骨细胞生成和破骨细胞生成；确定 这些影响直接针对细胞的程度 成骨细胞谱系；并确定这些的生理相关性 体内骨转换的代理。 合并的定义 这些激素在小鼠过程中的各自贡献 成骨细胞生成将提供有关其潜在相似的洞察力 在骑自行车和绝经后妇女中的作用。