COLONY STIMULATING FACTOR 1--REGULATION AND ROLE IN BONE

集落刺激因子 1——在骨中的调节和作用

• 批准号: 3246747
• 负责人: ELEANOR C WEIR
• 金额: $ 10.84万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-02-01 至 1995-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3246747
• 关键词: 1,25 dihydroxycholecalciferol; calcium; chickens; colony stimulating factor; cyclic AMP; gene expression; glycoprotein biosynthesis; growth factor receptors; hormone regulation /control mechanism; interleukin 1; laboratory mouse; laboratory rat; messenger RNA; northern blottings; nuclear runoff assay; osteoblasts; osteoclasts; osteoporosis; parathyroid hormones; physiologic bone resorption; protein kinase C; receptor expression; tissue /cell culture; tumor necrosis factor alpha; tumor necrosis factor beta; western blottings

Osteoporosis is a major public health problem among post-menopausal women and the elderly. It is characterized by a reduction in bone mass, and leads to fractures, skeletal deformities and chronic pain. Although the pathogenesis is complex, the fall in circulating estrogen levels at the time of menopause is an important etiologic factor. One effect of estrogen appears to be to protect the skeleton from the resorptive action of parathyroid hormone (PTH). Estrogen withdrawal at menopause thus increases the sensitivity of the skeleton to PTH, causing mobilization of calcium and bone loss. Therefore understanding the mechanism of bone-resorption, especially that induced by PTH, will be important to understanding the pathogenesis of osteoporosis. The cellular mechanisms of PTH-induced bone resorption are unclear. One hypothesis is that PTH-stimulated osteoblasts release cytokines which activate osteoclasts or osteoclast precursors. Although the nature of these cytokines is unknown, the colony stimulating factors (CSF's) may play an important role by stimulating proliferation of osteoclast precursors. Of the CSF's, only for colony stimulating factor-1 (CSF-1) is there convincing evidence supporting a role in bone remodelling. This evidence includes that deficiency of CSF-1 in vivo causes osteopetrosis in mice, - that CSF-1 stimulates osteoclast formation in vitro, and finally, our observation that CSF-1 is the principal colony stimulating activity secreted by osteoblasts in response to PTH. Although mounting evidence suggests a critical role for CSF-1 in osteoclast development, little is known about of its regulation and mechanism of action of bone. The goals of the present proposal are therefore: 1) to study the regulation of PTH-induced CSF-1 production in osteoblasts by examining the mechanism of PTH-induced up-regulation of CSF-1 gene expression, and by examining intra-cellular signalling mechanisms involved in CSF-1 secretion; 2) to examine CSF-1 production by osteoblasts in response to other bone-resorbing agents; 3) to determine the role of CSF-1 in bone resorption using organ culture systems; and 4) to characterize the expression of the CSF-1 receptor in osteoclasts, and examine its regulation by osteotropic agents. We expect that these studies will help clarify CSF-1's role in bone remodelling, which may be an important factor in the pathogenesis of osteoporosis.

骨质疏松症是绝经后妇女的主要公共卫生问题 和老人。 它的特征是骨骼质量减少，并且 导致骨折，骨骼畸形和慢性疼痛。 虽然 发病机理是复杂的，在循环的雌激素水平下降 更年期的时间是重要的病因。 雌激素的一种作用似乎是保护骨骼免受 甲状旁腺激素（PTH）的吸收作用。 雌激素提取 因此，更年期会增加骨骼对PTH的敏感性，从而导致 动员钙和骨质流失。 因此了解 骨吸附的机制，尤其是由PTH引起的机制，将是 重要的是了解骨质疏松症的发病机理。 PTH诱导的骨吸收的细胞机制尚不清楚。 一 假设是PTH刺激的成骨细胞释放细胞因子 激活破骨细胞或破骨细胞前体。 虽然本质 这些细胞因子尚不清楚，菌落刺激因素（CSF）可能会发挥作用 刺激破骨细胞前体的增殖的重要作用。 在CSF中，仅用于菌落刺激因子-1（CSF-1） 令人信服的证据支持在骨骼重塑中发挥作用。 这个证据 包括CSF -1体内CSF -1的缺乏会导致小鼠的骨质肌膜病， - CSF-1在体外刺激破骨细胞的形成，最后是我们的 观察CSF-1是主要菌落刺激活性 由成骨细胞分泌，以响应PTH。 尽管越来越多的证据表明CSF-1在破骨细胞中的重要作用 开发，对其调节和机制知​​之甚少 骨骼的作用。 因此，本提案的目标是：1） 研究PTH诱导的成骨细胞中PTH诱导的CSF-1产生的调节 检查PTH引起的CSF-1基因上调的机制 表达，并检查涉及的细胞内信号传导机制 在CSF-1分泌中； 2）检查成骨细胞中的CSF-1产生 对其他骨呈现剂的反应； 3）确定CSF-1的作用 在使用器官培养系统的骨吸收中； 4）表征 CSF-1受体在破骨细胞中的表达，并检查其调节 由骨骼剂。 我们希望这些研究将有助于阐明CSF-1在骨骼中的作用 重塑，这可能是对发病机理的重要因素 骨质疏松症。