FACTORS INFLUENCING BONE METABOLISM

描述：(改编自《调查者摘要》)前列腺素 (PGS)对骨形成既有促进作用也有抑制作用， 再吸收。这些影响可能在监管中发挥重要作用 由机械力引起的骨转换，与骨丢失有关 炎症和骨质疏松症的发病机制。这项建议是 重点研究了PGs对骨形成的影响。申请者将 检验以下假设：(1)刺激(合成代谢)效应 PGS的原因是复制和分化增加 成骨细胞前体细胞。其中一个涉及的受体是EP2 刺激循环AMP产生的职业。回应包括 增加内源性生长因子的生产或激活。(2) 对分化的成骨细胞有抑制(分解代谢)作用。它 涉及FP受体的激活和胶原基因的抑制 转录，通过蛋白激酶C(PKC)途径介导。(3)PGs 可诱导骨组织中前列腺素G/H合成酶(PGHS)基因的表达。这 自身扩增可持续增加内源性PG 瞬变扰动后的水平。回应可能是 合成代谢或分解代谢取决于受影响的细胞和PG 制作。 为了检验这些假设，研究人员将研究 外源性和内源性PGs对原代培养的啮齿动物颅骨细胞的影响 人骨细胞系和携带胶原启动子的转基因小鼠- 氯霉素乙酰转移酶报告构建。他们会 确定生长因子的作用并定义转录 胶原蛋白的调节元件。PGHS的自动扩增将是 细胞培养和体内研究及其构效关系 关系、信号转导机制与转录调控 检查过了。这些研究应该提高对PGs的作用的理解 在生理和病理上，也可能导致新的 骨骼的合成代谢剂。

DESCRIPTION: (Adapted from the Investigator's Abstract) Prostaglandins (PGs) have both stimulatory and inhibitory effects on bone formation and resorption. These effects are likely to be important in regulation of bone turnover by mechanical forces, in bone loss associated with inflammation and in the pathogenesis of osteoporosis. This proposal is focused on the effects of PGs on bone formation. The applicants will test the following hypotheses: (1) The stimulatory (anabolic) effect of PGs is due to an increase in replication and differentiation of osteoblast precursors. One of the receptors involved is of the EP2 class which stimulates cyclic AMP production. The response involves increased production or activation of endogenous growth factors. (2) The inhibitory (catabolic) effect is on differentiated osteoblasts. It involves activation of an FP receptor and inhibition of collagen gene transcription, mediated via a protein kinase C (PKC) pathway. (3) PGs can induce prostaglandin G/H synthase (PGHS) mRNA in bone. This autoamplification can produce sustained increases in endogenous PG levels after transient perturbations. The responses might be either anabolic or catabolic depending on the cells affected and the PGs produced. To test these hypotheses the investigators will study the effects of exogenous and endogenous PGs on cultured primary calvarial cells, rodent and human bone cell lines and transgenic mice bearing collagen promoter- chloramphenicol acetyl transferase reporter constructs. They will determine the role of growth factors and define transcriptional regulatory elements for collagen. Autoamplification of PGHS will be studied in cell culture and in vivo and its structure-activity relations, signal transduction mechanisms and transcriptional regulation examined. These studies should improve understanding of the role of PGs in physiology and pathology and might also lead to development of new anabolic agents for the skeleton.