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: 2144436
• 负责人: ELEANOR C WEIR
• 金额: $ 11.42万
• 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/2144436
• 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一个主要公共卫生问题 和老年人。 其特征在于骨量减少， 导致骨折骨骼畸形和慢性疼痛 虽然 发病机制是复杂的，在循环雌激素水平的下降， 绝经时间是重要的发病因素。 雌激素的一个作用似乎是保护骨骼免受 甲状旁腺激素（PTH）的吸收作用。 雌激素停药， 更年期因此增加了骨骼对PTH的敏感性， 钙动员和骨丢失。 因此， 骨吸收机制，特别是PTH诱导的骨吸收机制，将被 这对了解骨质疏松症的发病机制很重要。 PTH诱导骨吸收的细胞机制尚不清楚。 一 假设是PTH刺激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， 这些细胞因子是未知的，殖民地刺激因子（CSF's）可能发挥作用， 通过刺激破骨细胞前体的增殖而发挥重要作用。 在CSF中，只有集落刺激因子-1（CSF-1） 有令人信服的证据支持在骨重建中的作用。 这一证据 包括体内CSF-1的缺乏导致小鼠的骨硬化症， CSF-1在体外刺激破骨细胞的形成，最后， 观察到CSF-1是主要的集落刺激活性 由成骨细胞对PTH的反应分泌。 尽管越来越多的证据表明CSF-1在破骨细胞中起着关键作用， 发展，很少有人知道它的调控和机制， 骨的作用。 因此，本提案的目标是：1） 研究PTH诱导成骨细胞产生CSF-1的调节， 探讨PTH诱导CSF-1基因上调的机制 表达，并通过检查涉及的细胞内信号传导机制， 在CSF-1分泌中; 2）检测成骨细胞在 对其他骨吸收剂的反应; 3）确定CSF-1的作用 在骨吸收中使用器官培养系统;和4）表征 CSF-1受体在破骨细胞中的表达，并检查其调节 通过骨生长剂。 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，这可能是一个重要因素的发病机制， 骨质疏松