Mechanisms Mediating the Alcohol-Induced Reduction in Peak Bone Mass

描述(由申请人提供)：长期酗酒会导致骨质丢失，如果发生骨折，还会损害骨骼愈合。特纳(赞助商)实验室的研究表明，酒精对成年大鼠骨骼的有害影响部分是由于生长激素(GH)信号紊乱。除了直接的骨合成代谢作用外，生长激素还介导重要的成骨细胞生长因子-胰岛素样生长因子-L(IGF-I)在骨基质中的沉积。在破骨细胞的作用下，IGF-I从基质中释放出来，进而在骨重建过程中骨形成与骨吸收的偶联中起着关键作用。在成人中，生长激素通过调节骨形成和吸收之间的平衡来帮助维持骨量和质量。生长激素通过调节骨骼的净获取，在骨骼生长过程中起着额外的作用。饮酒，尤其是酗酒，在青少年中非常普遍。虽然这种行为通常是短暂的，不会导致酗酒，但它可能会对骨骼产生不良的长期后果。特纳实验室的长期目标是确定酒精滥用对骨骼影响的调节途径。我博士后研究的目标是检验酒精损害成骨细胞生长激素信号的假设。这一假说将在体外使用人类成骨细胞(hFOB细胞)进行验证，并在雄性青春期大鼠体内进行验证。这项研究的具体目的是：具体目标1：确定酒精对生长激素诱导的hFOB细胞增殖、分化、IGF-I合成和结节形成的剂量效应效应。这些研究将检验酒精对生长激素的骨骼合成代谢反应有直接抑制作用的假设。这一结果将为未来旨在揭示酒精抑制生长激素信号的详细分子机制(S)的研究奠定基础。具体目的2：测定酗酒对生长激素缺乏的青春期大鼠GH介导的成骨细胞分化和活性的影响。这些研究将检验这一假设，即青春期大鼠对酒精对骨形成的抑制作用非常敏感，因为它们需要高水平的生长激素。具体目标3：确定青少年长期酗酒对峰值骨量、骨基质中IGF-I水平、骨力学性质和骨转换的影响。这些研究将检验一种假设，即长期酗酒会降低骨基质中IGF-I的含量，而骨基质中的IGF-I含量反过来又与骨骼重塑和骨骼质量的损害有关，即使在戒酒后也是如此。这些新的研究将批判性地评估紊乱的生长激素在调节酒精对骨生长的有害影响中的作用，并将批判性地测试酒精损害的骨重建的可信机制。

DESCRIPTION (provided by applicant): Chronic alcohol abuse results in bone loss and, should a fracture occur, impaired bone healing. Studies in the Turner (sponsor) laboratory suggest that the detrimental effects of alcohol on bone in adult rats are due, in part, to disturbed growth hormone (GH) signaling. In addition to its direct bone anabolic effects, GH mediates the deposition of the important osteoblast growth factor, insulin-like growth factor-l (IGF-I), into bone matrix. The release of IGF-I from the matrix by the action of osteoclasts, in turn, plays a critical role in coupling of bone formation to bone resorption during bone remodeling. In the adult, GH helps maintain bone mass and quality by regulating the balance between bone formation and resorption. GH plays an additional role in the growing skeleton by regulating the net acquisition of bone. Alcohol consumption, especially binge drinking, is very common in adolescents. Although this behavior is generally transient and does not lead to alcoholism, it nevertheless can have undesirable long-term consequences to the skeleton. The long-term goal of the Turner laboratory is to identify pathways mediating skeletal effects of alcohol abuse. The goal of my postdoctoral research is to test the hypothesis that alcohol impairs GH signaling in osteoblasts. This hypothesis will be tested in vitro using human osteoblasts (hFOB cells) and in vivo in male adolescent rats. The specific aims of the proposed research are to: Specific Aim 1: Determine the dose response effects of alcohol on GH-mediated increases in proliferation, differentiation, IGF-I synthesis and nodule formation by hFOB cells. These studies will test the hypothesis that alcohol has a direct inhibitory effect on the bone anabolic response to GH. The results will set the stage for future studies directed toward uncovering the detailed molecular mechanism(s) by which alcohol inhibits GH signaling. Specific Aim 2: Measure the effects of binge drinking on GH-mediated stimulation of osteoblast differentiation and activity in GH-deficient hypophysectomized adolescent rats. These studies will test the hypothesis that adolescent rats are very sensitive to the inhibitory effects of alcohol on bone formation because of their requirement for high levels of GH. Specific Aim 3: Determine the long-duration effects of chronic adolescent binge drinking on peak bone mass, IGF-I levels in bone matrix, bone mechanical properties and turnover. These studies will test the hypothesis that chronic binge drinking reduces the content of IGF-I in bone matrix which, in turn, is associated with impairment of bone remodeling and bone quality even after alcohol is withdrawn. These novel studies will critically evaluate the role of disturbed GH in mediating the detrimental effects of alcohol on bone growth and will critically test a plausible mechanism for alcohol-impaired bone remodeling.