The Role of OPG in GATA-1 Deficiency

描述(由申请人提供)： 骨质疏松症是一个主要的公共健康问题，50岁以上的女性中有1/2会患上骨质疏松症 骨质疏松性骨折(国家骨质疏松基金会)。骨质疏松症是由于骨骼动态平衡的改变造成的，骨吸收超过了骨形成。我们发现，缺乏GATA-1的小鼠具有高骨量表型(骨体积增加3倍)。GATA-1是正常巨核细胞发育所需的转录因子。这种意想不到的骨体积增加说明了造血系统和骨骼系统之间的密切关系。 最近，8个家系被确认为GATA-1错义突变(功能丧失突变) 导致X连锁的血小板减少症。受影响的个体有各种各样的血液学表现，类似于GATA-1缺陷小鼠。基于这些数据，我们的假设是，携带GATA-1功能缺失突变的小鼠和人类具有高骨量表型。我们的第二个假设是，骨保护素水平随着GATA-1缺乏而增加，高水平的骨保护素有助于高骨量表型。以下目标将检验这些假设。在特定目的I中，我们将使用双能X射线骨密度仪评估GATA-1感染、携带者和对照家庭成员的骨密度。在特定的目标2中，我们将描述GATA-1感染、携带者和对照家庭成员骨转换的生化标志物的特征。在特定目的III中，我们将研究GATA-1感染、携带者和对照家庭成员的外周血单核细胞的破骨细胞分化潜能。最后，在特定的目标IV中，我们将确定骨保护素是否与GATA-1缺乏所见的高骨量表型有关。这项翻译研究将进一步证明利用小鼠模型更好地了解人类疾病的价值。此外，这项研究将显示GATA-1基因表达如何与骨转换相关，以及骨保护素是否与骨量增加有关。因此，这些研究涉及：1)巨核细胞相关性疾病，如血小板减少、血小板增多症、血小板减少和特发性骨髓纤维化；2)基因表达与人类疾病；3)骨量调节的新途径(S)；4)骨丢失疾病，如骨质疏松。

DESCRIPTION (provided by applicant): Osteoporosis is a major public health problem, in which 1 in 2 women over the age of 50 will have an osteoporotic fracture (National Osteoporosis Foundation). Osteoporosis results from an alteration in skeletal homeostasis, whereby bone resorption exceeds formation. We have found that mice deficient in GATA-1, a transcription factor required for normal megakaryocyte development, have a high bone mass phenotype (>3-fold increase in bone volume). This unexpected increase in bone volume speaks to the intimate relationship between the hematopoietic and skeletal system. Recently, 8 families have been identified with GATA-1 missense mutations (loss-of-function mutations) which result in X-linked thrombocytopenia. Affected individuals have a variety of hematologic manifestations which resemble GATA-1 deficient mice. Based on this data it is our hypothesis that mice and humans with GATA-1 loss-of-function mutations have a high bone mass phenotype. Our secondary hypothesis is that osteoprotegerin levels are increased with GATA-1 deficiency and that high osteoprotegerin levels contribute to the high bone mass phenotype. The following Aims will test these hypotheses. In Specific Aim I we will evaluate the bone mineral density in GATA-1 affected, carrier, and control family members using dual energy X-ray absorptiometry. In Specific Aim II we will characterize the biochemical markers of bone turnover in GATA-1 affected, carrier, and control family members. In Specific Aim III we will investigate the osteoclastogenic potential of peripheral blood mononuclear cells from GATA-1 affected, carrier, and control family members. Finally, in Specific Aim IV we will determine whether osteoprotegerin contributes to the high bone mass phenotype seen with GATA-1 deficiency. This translational study will further demonstrate the value of utilizing mouse models to better understand human disease. In addition, this study will show how GATA-1 gene expression correlates with bone turnover and whether osteoprotegerin is responsible for the increased bone mass. Therefore, these studies are relevant to: 1) Megakaryocyte associated diseases, such as thrombocytopenia, thrombocytosis, thrombasthenia, and idiopathic myelofibrosis; 2) Gene expression and human disease; 3) New pathway(s) of bone mass regulation; and 4) Bone loss diseases, such as osteoporosis.