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 ¹, Melissa A. Kacena ¹, Sarah E. Tague ¹, Jinxi Wang ¹, Mark C. Horowitz ¹ and H. Clarke Anderson ^1*

¹ University of Kansas Medical Center, Kansas City, Kansas (RG,SET,JW,HCA), and Yale University School of Medicine, New Haven, Connecticut (MAK,MCH)

^* To whom correspondence should be addressed. E-mail: handerso{at}kumc.edu.

Submitted on December 14, 2006
Accepted on 1 March 2007

	Abstract

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 that is 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. Results: Marrow MKs from both wild-type and GATA-1^low mice showed moderate to intense staining for BMP-2, BMP-4, BMP-6 and BMPR-IA and BMPR-II, while 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 reduced number of functional osteoclasts, since the number of tartarate-resistant acid phosphatase positive (TRAP⁺) osteoclasts was greater in GATA-1^low mice than in controls. Conclusions: Our findings demonstrate the presence of significant amounts of BMP-2, BMP-4, and BMP-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.

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

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