AbstractMyelofibrosis and osteosclerosis are prominent features arising in mice overexpressing thrombopoietin (TPO). The pivotal role of transforming growth factor β1 (TGF-β1) 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 anopg−/− or WT background for long-term reconstitution. The 4 combinations of graft/host (WT/WT,opg−/−/opg−/−,opg−/−/WT, and WT/opg−/−) were studied. Elevation of TPO and TGF-β1 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.