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Prepublished online as a Blood First Edition Paper on December 27, 2002; DOI 10.1182/blood-2002-09-2839. This Article Full Text (PDF) All Versions of this Article: 2002-09-2839v1 101/8/2983    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chagraoui, H. Articles by Wendling, F. Search for Related Content PubMed PubMed Citation Articles by Chagraoui, H. Articles by Wendling, F. Social Bookmarking                   What's this? Submitted September 19, 2002 Accepted December 13, 2002 Stimulation of osteoprotegerin production is responsible for osteosclerosis in mice overexpressing TPO Hedia Chagraoui, Micheline Tulliez, Tarek Smayra, Emiko Komura, Stephane Giraudier, Theodore Yun, Nathalie Lassau, William Vainchenker*, and Francoise Wendling IFR 54-INSERM U 362, Institut Gustave Roussy, Villejuif, France Service Anatomie et Cytologie Pathologiques, Hopital Cochin, Paris, France LIPA, IFR 54, Institut Gustave Roussy, Villejuif, France Department of Immunology, University of Washington, Seattle, WA, USA * Corresponding author; email: verpre{at}igr.fr. Myelofibrosis and osteosclerosis are prominent features arising in mice overexpressing thrombopoietin (TPO). The pivotal role of TGF-1 in the pathogenesis of myelofibrosis has been documented, but the mechanisms mediating osteosclerosis remain unclear. Here, we used mice deficient in osteoprotegerin (OPG), a secreted inhibitor of bone resorption to determine whether osteosclerosis occurs through a deregulation of osteoclastogenesis. Marrow cells from opg-deficient mice (opg-/-) or wild-type (WT) littermates were infected with a retrovirus encoding TPO and engrafted into an opg-/- or WT background for long-term reconstitution. The four combinations of graft/host (WT/WT, opg-/-/opg-/-,opg-/-/WT and WT/opg-/-) were studied. Elevation of TPO and TGF-1 levels in plasma was similar in the 4 experimental groups and all the mice developed a similar myeloproliferative syndrome associated with severe myelofibrosis. Osteosclerosis developed in WT hosts engrafted with WT or opg-/- hematopoietic cells and was associated with increased OPG levels in plasma and decreased osteoclastogenesis. In contrast, opg-/- hosts exhibited an osteoporotic phenotype and a growth of bone trabeculae was rarely seen. These findings suggest that osteosclerosis in mice with TPO overexpression occurs predominantly via an up-regulation of OPG in host stromal cells leading to disruption of osteoclastogenesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. Garimella, M. A. Kacena, S. E. Tague, J. Wang, M. C. Horowitz, and H. C. Anderson Expression of Bone Morphogenetic Proteins and Their Receptors in the Bone Marrow Megakaryocytes of GATA-1low Mice: A Possible Role in Osteosclerosis J. Histochem. Cytochem., July 1, 2007; 55(7): 745 - 752. [Abstract] [Full Text] [PDF] M. S. Cairo Myelofibrosis with myeloid metaplasia: targeted therapy Blood, July 1, 2007; 110(1): 2 - 3. [Full Text] [PDF] O. Wagner-Ballon, D. F. Pisani, T. Gastinne, M. Tulliez, R. Chaligne, C. Lacout, F. Aurade, J.-L. Villeval, P. Gonin, W. Vainchenker, et al. 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