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卫生问题，其中50岁以上的妇女中有1/2将患有骨质疏松症。 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内稳态的改变，骨吸收超过骨形成。我们发现，加塔-1（一种正常巨核细胞发育所需的转录因子）缺陷的小鼠具有高骨量表型（骨体积增加>3倍）。这种骨体积的意外增加说明了造血系统和骨骼系统之间的密切关系。 最近，8个家庭已确定与加塔-1错义突变（功能丧失突变） 导致X连锁血小板减少症受影响的个体具有类似于加塔-1缺陷小鼠的多种血液学表现。基于这些数据，我们假设具有加塔-1功能丧失突变的小鼠和人具有高骨量表型。我们的第二个假设是骨保护素水平随着加塔-1缺乏而增加，并且高骨保护素水平有助于高骨量表型。以下目标将检验这些假设。在特定目标I中，我们将使用双能X线吸收测定法评价加塔-1受影响、携带者和对照家族成员的骨密度。在特定目标II中，我们将描述加塔-1受影响、携带者和对照家族成员中骨转换的生化标志物。在特定目标III中，我们将研究来自加塔-1受影响、携带者和对照家族成员的外周血单核细胞的破骨细胞生成潜能。最后，在具体目标IV中，我们将确定骨保护素是否有助于加塔-1缺乏症患者的高骨量表型。这项转化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，本研究将显示加塔-1基因表达与骨转换的关系，以及骨保护素是否与骨量增加有关。因此，这些研究涉及：1）巨核细胞相关疾病，如血小板减少症、血小板增多症、血小板无力症和特发性骨髓纤维化; 2）基因表达和人类疾病; 3）骨量调节的新途径;以及4）骨丢失疾病，如骨质疏松症。

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.