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.
| Meijome, Tomas E; Hooker, R Adam; Cheng, Ying-Hua et al. (2015) GATA-1 deficiency rescues trabecular but not cortical bone in OPG deficient mice. J Cell Physiol 230:783-90 |
| Cheng, Ying-Hua; Streicher, Drew A; Waning, David L et al. (2015) Signaling pathways involved in megakaryocyte-mediated proliferation of osteoblast lineage cells. J Cell Physiol 230:578-86 |
| Cheng, Ying-Hua; Hooker, R Adam; Nguyen, Khanh et al. (2013) Pyk2 regulates megakaryocyte-induced increases in osteoblast number and bone formation. J Bone Miner Res 28:1434-45 |
| Kacena, Melissa A; Gundberg, Caren M; Kacena 3rd, William J et al. (2013) The effects of GATA-1 and NF-E2 deficiency on bone biomechanical, biochemical, and mineral properties. J Cell Physiol 228:1594-600 |
| Kacena, Melissa A; Eleniste, Pierre P; Cheng, Ying-Hua et al. (2012) Megakaryocytes regulate expression of Pyk2 isoforms and caspase-mediated cleavage of actin in osteoblasts. J Biol Chem 287:17257-68 |
| Bethel, Monique; Srour, Edward F; Kacena, Melissa A (2011) Hematopoietic cell regulation of osteoblast proliferation and differentiation. Curr Osteoporos Rep 9:96-102 |
| Millikan, Patrick D; Balamohan, Sanjeev M; Raskind, Wendy H et al. (2011) Inherited thrombocytopenia due to GATA-1 mutations. Semin Thromb Hemost 37:682-9 |
| Lemieux, Justin M; Wu, Gary; Morgan, Joseph A et al. (2011) DMSO regulates osteoclast development in vitro. In Vitro Cell Dev Biol Anim 47:260-7 |
| 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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