Mechanisms of Alcohol-Induced Hepatic Osteodystrophy

 描述(申请人提供)：长期酗酒易导致骨折，但其原因尚不清楚。营养和激素缺乏被认为会增加骨折的风险，但将酗酒者与健康对照组进行比较的研究往往没有显示出显着差异。因此，可能还涉及其他因素。骨稳态的一个重要特征是干细胞需要不断分化为成骨细胞，成骨细胞是负责新骨形成的细胞。影响骨骼完整性的单基因疾病可以揭示调节干细胞向成骨细胞分化的新因素。最近，导致色素上皮衍生因子(PEDF)完全缺失的基因突变被认为是VI型成骨不全(OI)的原因，OI是一种常染色体隐性遗传病，以严重的骨质虚弱和早期骨折为特征。我们先前发表的PEDF KO小鼠概括了人类OI VI型表型，在幼鼠中有明显的骨小梁丢失。我们进一步证明，PEDF引导了一条关键的信号通路，该通路负责干细胞分化为成骨细胞而不是脂肪细胞。基于这种人类疾病，我们将PEDF定义为一种新的成骨细胞分化因子。在本申请中概述的研究将调查PEDF是否可以挽救在两种具有良好特征的酒精喂养模型中发生的骨丢失。我们还将研究介导新的成骨细胞形成的信号通路。最后，我们与OI V型和VI型患者的临床医生进行了合作。可诱导的多能干细胞将从这些患者中产生。然后，我们将评估这些PEDF缺失的干细胞是否能正常分化为骨细胞。这一应用的发现可能有助于定义能够模仿PEDF对骨细胞分化的作用的分子。

 DESCRIPTION (provided by applicant): Chronic alcohol abuse predisposes to bone fractures but why this happens is unclear. Nutritional and hormonal deficiencies have been postulated to increase fracture risk but studies comparing alcoholics to healthy controls have often not shown significant differences. Thus, other factors are likely involved. A critical feature of bone homeostasis is the need for continual differentiation of stem cells to osteoblasts, the cells responsible for new bone formation. Single gene diseases that impact bone integrity can shed light on novel factors that regulate stem cell differentiation to osteoblasts. Recently, gene mutations that result in complete absence of pigment epithelium-derived factor (PEDF) have been identified as the cause of Osteogenesis Imperfecta (OI) Type VI, an autosomal recessive disease characterized by severely weakened bone and early fractures. We previously published that PEDF KO mice recapitulate the human OI Type VI phenotype with marked trabecular bone loss in young mice. We further showed that PEDF directs a key signaling pathway that is responsible for stem cell differentiation to osteoblasts and away from adipocytes. Based on this human disease, we have defined PEDF as a novel osteoblast differentiation factor. The studies outlined in this application will investigate whether PEDF can rescue the bone loss that occurs in two well-characterized models of alcohol feeding. We will also investigate the signaling pathways that mediate new osteoblast formation. Finally, we have collaborations with clinicians who have OI Type V and VI patients. Inducible pluripotent stem cells will be created from these patients. We will then assess whether these PEDF-null stem cells can differentiate normally to bone cells. Findings from this application may be helpful in defining molecules that can mimic PEDF's actions on bone cell differentiation.