Mechanisms of Alcohol-Induced Hepatic Osteodystrophy

 描述（由申请人提供）：长期酗酒易导致骨折，但原因尚不清楚。营养和激素缺乏被认为会增加骨折的风险，但对酗酒者和健康对照者的研究往往没有显示出显着差异。因此，可能涉及其他因素。骨稳态的一个关键特征是需要干细胞持续分化为成骨细胞，成骨细胞负责新骨形成。影响骨完整性的单基因疾病可以揭示调节干细胞分化为成骨细胞的新因子。最近，导致完全缺乏色素上皮衍生因子（PEDF）的基因突变已被确定为VI型成骨不全（OI）的原因，VI型成骨不全是一种常染色体隐性遗传疾病，其特征是骨严重弱化和早期骨折。我们先前发表了PEDF KO小鼠重现了人OI VI型表型，在年轻小鼠中具有显著的骨小梁丢失。我们进一步表明，PEDF指导一个关键的信号通路，负责干细胞分化成骨细胞和远离脂肪细胞。基于这一人类疾病，我们将PEDF定义为一种新的成骨细胞分化因子。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成骨细胞形成的信号通路。最后，我们与患有OI V型和VI型患者的临床医生合作。诱导性多能干细胞将从这些患者中产生。然后，我们将评估这些无PEDF的干细胞是否可以正常分化为骨细胞。从这个应用程序的发现可能有助于定义分子，可以模仿PEDF的作用，对骨细胞分化。

 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.