? 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. ? ? ?
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| Kacena, Melissa A; Ciovacco, Wendy A (2010) Megakaryocyte-bone cell interactions. Adv Exp Med Biol 658:31-41 |
| Lemieux, Justin M; Horowitz, Mark C; Kacena, Melissa A (2010) Involvement of integrins alpha(3)beta(1) and alpha(5)beta(1) and glycoprotein IIb in megakaryocyte-induced osteoblast proliferation. J Cell Biochem 109:927-32 |
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