COLONY STIMULATING FACTOR 1 REGULATION AND ROLE IN BONE

成骨细胞介导破骨细胞性骨的确切机制 再吸收尚不清楚。一个被广泛接受的假说是，激活 成骨细胞分泌细胞因子，直接或间接影响 破骨细胞的形成或功能。尽管这些推定的性质 细胞因子是未知的，令人信服的体内和体外数据已经出现 支持集落刺激因子-1(CSF-1)作为 成骨细胞衍生因子参与破骨细胞的形成。因此，在 在体内，OP/OP骨质疏松症小鼠中缺乏CSF-1导致 体外破骨细胞形成和骨吸收的失败 研究表明，csf-1在细胞增殖中起关键作用。 和破骨细胞前体细胞的分化，由CSF-1刺激 胎鼠掌骨实验中的骨吸收，以及脑脊液-1 破骨细胞上存在受体。脑脊液-1被合成为一种可溶性的 或细胞表面蛋白，虽然我们知道成骨细胞合成 两种形式的CSF-1 I的构成和对趋骨性的反应 药剂，对它们在骨骼中的生理意义知之甚少 改建。此外，虽然我们知道两种关键的促骨剂， 甲状旁腺激素和肿瘤坏死因子升高 成骨细胞表达脑脊液细胞因子-1的确切机制 他们到底做了什么还不清楚。最后，精确的生理作用 CSF-1在体内骨重建中的作用尚不清楚。这样做的长期目标是 因此，建议是：1.定义细胞的生理作用- 骨中表面和可溶形式的脑脊液-1，通过检测 细胞表面CSF-1对破骨细胞信号转导的影响 两个品系的转基因小鼠，每个品系都缺乏一种 Csf-1I亚型；2.通过以下方法来表征细胞机制 哪种肿瘤坏死因子和甲状旁腺激素通过促进成骨细胞中CSF-1的转录 介导肿瘤坏死因子诱导的脑脊液-1的核因子-kappaB蛋白的特性 基因表达及对CSF-1启动子的鉴定和鉴定 PTH介导这一反应的因素；以及3.分析 脑脊液-1在体内骨重建中的作用 体外靶向过表达CSF-1的转基因小鼠模型的建立 在成骨细胞中。 这些研究将有助于阐明A蛋白的调节和作用 破骨细胞发育中关键的细胞因子，并将改善 我们对生理性骨吸收机制的理解，以及 是由促骨剂引起的。

The precise mechanism whereby osteoblasts mediate osteoclastic bone resorption is unclear. One widely-held hypothesis is that activated osteoblasts secrete cytokines that directly or indirectly influence osteoclast formation or function. Although the nature of these putative cytokines is unknown, compelling in vivo and in vitro data have emerged to support a role for colony-stimulating factor-1 (CSF-1) as an osteoblast-derived factor involved in osteoclast formation. Thus, in vivo, deficiency of CSF-1 in the op/op osteopetrotic mouse causes a failure of osteoclast formation and bone resorption while in vitro studies have demonstrated that CSF-1 is critical for the proliferation and differentiation of osteoclast progenitors, that CSF-1 stimulates bone resorption in the fetal mouse metacarpal assay, and that CSF-1 receptors are present on osteoclasts. CSF-1 is synthesized as a soluble or cell surface protein, and while we know that osteoblasts synthesize both forms of CSF-1 I constitutively and in response to osteotropic agents, little is known of their physiologic significance in bone remodeling. Additionally, while we know that two key osteotropic agents, parathyroid hormone (PTH) and tumor necrosis factor (TNF) increase expression of the CSF-1 gene in osteoblasts, the precise mechanism by which they do so is unclear. Finally, the precise physiologic role of CSF-1 in bone remodeling in vivo is unknown. The long term goals of this proposal are therefore: 1. to define the physiologic roles of the cell- surface and soluble forms of CSF-1 in bone, by examining the effects of cell-surface CSF-1 on osteoclast signaling in vitro, and by generating two lines of genetically-altered mice that are each deficient in one of the CSF-1 I isoforms; 2. to characterize the cellular mechanisms by which TNF and PTH increase CSF-1 transcription in osteoblasts by characterizing the NF-kappaB proteins that mediate TNF-induced CSF-1 gene expression and by identifying and characterizing the CSF-1 promoter elements by which PTH mediates this response; and 3. to analyze the role of CSF-1 in bone remodeling in vivo by characterizing in vivo and in vitro a transgenic mouse model with targeted overexpression of CSF-1 in osteoblasts. These studies will help to elucidate the regulation and role of a cytokine which is critical in osteoclast development, and will improve our understanding of the mechanisms of physiologic bone resorption, and that induced by osteotropic agents.