COLONY STIMULATING FACTOR 1--REGULATION AND ROLE IN BONE

描述：(改编自《调查人员摘要》)成骨细胞，在 除了形成骨，在骨吸收中起着核心作用。 尽管成骨细胞介导破骨细胞的确切机制 骨吸收尚不清楚，一个被广泛接受的假设是，在 对骨吸收药物的反应，成骨细胞分泌细胞因子 激活破骨细胞或其前体细胞。虽然这些东西的性质 细胞因子未知，一个潜在的候选者是集落刺激 因子-1(CSF-1)。有大量的体内和体外证据表明 CSF-1对肿瘤细胞的增殖和增殖都至关重要 破骨细胞前体细胞的分化：(1)脑脊液-1缺乏 Vivo引起OP/OP小鼠的骨化病；(2)CSF-1刺激 破骨细胞的形成和骨吸收；以及(3)CSF-1是 成骨细胞分泌的主要集落刺激活性 甲状旁腺激素(PTH)。尽管有越来越多的证据表明 成骨细胞来源的脑脊液-1‘S在破骨细胞发育中的作用，很少是 已知成骨细胞中CSF-1基因表达的调节， 或由人合成和分泌的脑脊液-1的亚型 成骨细胞。此外，脑脊液中脑脊液的确切生理作用 人们对正常的骨重建知之甚少。 申请者最近证明了肿瘤坏死因子 肿瘤坏死因子(TNF)和甲状旁腺激素(PTH)促进脑脊液中CSF-1基因表达和蛋白释放 成骨细胞通过转录机制。他们计划追求这些 甲状旁腺激素和肿瘤坏死因子顺式作用元件的研究 诱导CSF-1基因表达并检测潜在转录 调节这一反应的因素，使用缺失的组合 分析和核蛋白-DNA结合研究。他们还拥有 流式细胞术和逆转录-DNA聚合酶链式反应分析证实 转录的RNA成骨细胞表达一种细胞表面形式的CSF-1， 经肿瘤坏死因子治疗后，其表达增加。因此，他们将延长这一期限 通过检测相关的表达、调节和 可溶性和细胞表面形式的csf-1的生物学意义。 在这些研究中，他们将确定信使核糖核酸和蛋白质的种类。 在未经处理的情况下合成、加工和释放的 肿瘤坏死因子处理的成骨细胞，并将检测可溶性和 破骨细胞形成过程中脑脊液-1的细胞表面形态最后，他们会 通过发展和研究CSF-1在体内骨重建中的作用 一只靶向过表达脑脊液-1的转基因小鼠的分析 成骨细胞。综上所述，这些研究应该澄清脑脊液-1‘S 在骨骼中的调节和作用，可能会提高对基础知识的理解 骨吸收的机制。

DESCRIPTION: (Adapted From Investigator's Abstract) The osteoblast, in addition to forming bone, plays a central role in bone resorption. Although the precise mechanism by which osteoblasts mediate osteoclastic bone resorption is unclear, one widely held hypothesis is that in response to bone resorbing agents, osteoblasts secrete cytokines which activate osteoclasts or their precursors. While the nature of these cytokines is unknown, one potential candidate is colony stimulating factor-1 (CSF-1). There is substantial in vivo and in vitro evidence that CSF-1 is critically important for both the proliferation and differentiation of osteoclast progenitors: (1) deficiency of CSF-1 in vivo causes osteopetrosis in the op/op mouse; (2) CSF-1 stimulates osteoclast formation and bone resorption in vitro; and (3) CSF-1 is the principal colony stimulating activity secreted by osteoblasts in response to parathyroid hormone (PTH). Although there is mounting evidence for osteoblast-derived CSF-1's role in osteoclast development, little is known regarding the regulation of CSF-1 gene expression in osteoblasts, or the isoforms of CSF-1 which are synthesized and secreted by osteoblasts. In addition, the precise physiologic role of CSF-1 in normal bone remodeling is poorly understood. The applicants have recently demonstrated that tumor necrosis factor (TNF) and PTH increase CSF-1 gene expression and protein release in osteoblasts by a transcriptional mechanism. They plan to pursue these observations by characterizing cis acting elements by which PTH and TNF induce CSF-1 gene expression, and examining potential transcription factors mediating this response, using a combination of deletional analysis and nuclear protein-DNA binding studies. They have also demonstrated by flow cytometry and by PCR analysis of reverse- transcribed RNA that osteoblasts express a cell surface form of CSF-1, which is increased by TNF treatment. They will, therefore, extend this observation by examining the relative expression, regulation and biological significance of the soluble and cell surface forms of CSF-1. For these studies they will characterize the mRNA and protein species of CSF-1 which are synthesized, processed and released by untreated and TNF-treated osteoblasts, and will examine the effects of the soluble and cell-surface forms of CSF-1 on osteoclast formation. Finally, they will examine the role of CSF-1 in bone remodeling in vivo by developing and analyzing a transgenic mouse with targeted over-expression of CSF-1 in osteoblasts. Taken together, these studies should elucidate CSF-1's regulation and role in bone and may improve the understanding of basic mechanisms of bone resorption.