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Expression of Bone Morphogenetic Proteins and Their Receptors in the Bone Marrow Megakaryocytes of GATA-1^low Mice: A Possible Role in Osteosclerosis

Rama Garimella, Melissa A. Kacena, Sarah E. Tague, Jinxi Wang, Mark C. Horowitz and H. Clarke Anderson

University of Kansas Medical Center, Kansas City, Kansas (RG,SET,JW,HCA), and Yale University School of Medicine, New Haven, Connecticut (MAK,MCH)

Correspondence to: H. Clarke Anderson, M.D., Department of Pathology, University of Kansas Medical Center, Kansas City, KS 66160. E-mail: handerso{at}kumc.edu

The mechanism of osteosclerosis associated with myelofibrosis in megakaryocyte (MK)-related myeloproliferative disorders is largely unknown. However, growth factors released from the bone marrow cells, including from MKs, have been implicated in myelofibrosis, osteosclerosis, and angiogenesis. GATA-1 is a transcription factor required for normal MK development. GATA-1 deficiency in mice (GATA-1^low) leads to increased megakaryocytic proliferation, followed by osteosclerosis and myelofibrosis. In this study we investigated the expression of bone morphogenetic proteins (BMPs) and BMP receptors and their possible role in the development of osteosclerosis in the MKs of 12-month-old GATA-1^low mice by immunohistochemistry, cytomorphometry, and quantitative real-time PCR. Marrow MKs from both wild-type and GATA-1^low mice showed moderate to intense staining for BMP-2, -4, and -6 and BMPR-IA and BMPR-II, whereas splenic MKs showed no BMP immunostaining. Presence of BMP protein in the bone marrow of GATA-1^low mice was more than that seen in controls, owing to an increased number of MKs and osteoblasts. The osteosclerosis seen in GATA-1^low mice appeared not to be due to a reduced number of functional osteoclasts because the number of tartrate-resistant acid phosphatase-positive osteoclasts was greater in GATA-1^low mice than in controls. Our findings demonstrate the presence of significant amounts of BMP-2, -4, and -6 along with their receptors in bone marrow MKs of WT and GATA-1^low mice. The increased levels of BMPs appear to be a result of increased numbers of MKs in GATA-1^low mice and may, in part, account for the stimulation of osteoblastic activity and resulting osteosclerosis. (J Histochem Cytochem 55:745–752, 2007)

Key Words: bone morphogenetic proteins • GATA-1 • megakaryocytes • osteoblasts • osteosclerosis • myelofibrosis

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