Dose Response Effects of Alcohol on Bone Metabolism

描述(申请人提供)：慢性酗酒人数最多 骨质疏松症的重要“生活方式”危险因素。中国的长期目标是 提出的研究是为了了解细胞和分子机制。 负责调解酒精对骨骼的有害行为， 有了这样的认识，才能制定有效的对策。 在当前资金间隔期间进行的研究提供了强有力的证据 酒精引起的骨丢失是由于骨重建的紊乱。 周而复始。具体地说，骨形成与骨形成之间的不平衡 普遍的骨吸收速度造成不足的新骨来补偿 用于骨吸收，导致骨净流失。在分子水平上，我们 已经在骨形成和骨形成之间建立了明确的正相关关系 胰岛素样生长因子-1(IGF-1)基因在骨组织中的表达 此外，胫骨的结构、细胞和基因表达发生了变化。 喂食酒精的大鼠与切除脑下垂体后的大鼠惊人地相似 (HYPOX)，提示骨骼反应的潜在机制 酒精滥用和生长激素(GH)缺乏是相似的。因为大多数人 生长激素对骨细胞的作用是由局部产生的IGF-1介导的。 酗酒和生长激素缺乏对骨骼的有害影响可能是共同的 干扰IGF-1信号转导是一种常见途径。的拮抗作用 甲状旁腺激素(PTH)可逆转HYPOX对骨形成的影响， 上调骨细胞IGF-1的表达。基于这些发现，我们的 工作假说是酒精引起的骨质疏松症主要是由于 成骨细胞减少IGF-1的表达，并可被预防或逆转 甲状旁腺素治疗。我们建议在成人和青少年中检验这些假设。 通过测定骨骼和骨骼的变化建立慢性酒精滥用雌性大鼠模型 HYPOX和正常饮酒大鼠的矿物质代谢：(2)HYPOX和 给予酒精和生长激素治疗的正常大鼠；(3)HYPOX和正常大鼠 酒精+IGF-1处理；(4)HYPOX+正常大鼠 (5)正常大鼠灌胃酒精诱导 骨丢失后行甲状旁腺激素治疗。一套互补的技术将 在这些实验中被用来评估骨骼变化，包括 动态和静态骨组织形态计量学，骨密度计量学，微型CT， 生化标记物、机械测试、免疫组织化学、放射自显影 用Northern杂交和核糖核酸酶保护实验进行RNA分析。

DESCRIPTION (provided by applicant): Chronic alcohol abuse is the most important "life style" risk factor for osteoporosis. The long-term goal of the proposed research is to understand the cellular and molecular mechanisms responsible for mediating alcohol's detrimental actions on the skeleton and, with this improved understanding, to develop effective countermeasures. Research performed during the current funding interval provides strong evidence that alcohol-induced bone loss is due to a disturbance in the bone remodeling cycle. Specifically, an imbalance in the coupling of bone formation to the prevailing rate of bone resorption creates inadequate new bone to compensate for bone resorption, resulting in net bone loss. At the molecular level, we have established a clear positive association between bone formation and insulin-like growth factor-I (IGF-1) gene expression in bone tissue. Furthermore, the architectural, cellular and gene expression changes in tibiae of rats fed alcohol are strikingly similar to those that follow hypophysectomy (HYPOX), suggesting that the underlying mechanisms for the skeletal response to alcohol abuse and growth hormone (GH) deficiency are similar. Because most of the effects of GH on bone cells are mediated by locally produced IGF-1, the detrimental skeletal effects of alcohol abuse and GH deficiency may share disturbed IGF-1 signaling as a common pathway. The antagonistic effects of HYPOX on bone formation can be reversed with parathyroid hormone (PTH), which up-regulates IGF-1 expression by bone cells. Based on these findings, our working hypotheses are that alcohol-induced osteoporosis is largely due to decreased IGF-1 expression by osteoblasts, and can be prevented or reversed by treatment with PTH. We propose to test these hypotheses in adult and adolescent female rat models for chronic alcohol abuse by determining changes in bone and mineral metabolism in: (1) HYPOX and intact rats fed alcohol; (2) HYPOX and intact rats fed alcohol and treated with GH; (3) HYPOX and intact rats fed alcohol and treated with IGF-1; and (4) HYPOX and intact rats simultaneously fed alcohol and treated with PTH; and (5) intact rats fed alcohol to induce bone loss and then treated with PTH. A suite of complementary techniques will be employed in these experiments to evaluate the skeletal changes, including dynamic and static bone histomorphometry, bone densitometry, micro-CT, biochemical markers, mechanical testing, immunohistochemistry, radioautography and RNA analysis by Northern blots and RNase protection assays.