The Role of OPG in GATA-1 Deficiency

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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.