title: Stimulation of osteoprotegerin production is responsible for osteosclerosis in mice overexpressing TPO.
abstract: Myelofibrosis and osteosclerosis are prominent features arising in mice overexpressing thrombopoietin (TPO). The pivotal role of transforming growth factor beta 1 (TGF-beta 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 4 combinations of graft/host (WT/WT, opg(-/-)/opg(-/-), opg(-/-)/WT, and WT/opg(-/-)) were studied. Elevation of TPO and TGF-beta 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.
authors.affiliation: IFR 54-INSERM U 362, Institut Gustave Roussy, Villejuif, France.
authors.forename: Hédia
authors.initials: H
authors.lastname: Chagraoui
authors.forename: Micheline
authors.initials: M
authors.lastname: Tulliez
authors.forename: Tarek
authors.initials: T
authors.lastname: Smayra
authors.forename: Emiko
authors.initials: E
authors.lastname: Komura
authors.forename: Stéphane
authors.initials: S
authors.lastname: Giraudier
authors.forename: Theodore
authors.initials: T
authors.lastname: Yun
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lassau
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.forename: Françoise
authors.initials: F
authors.lastname: Wendling
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D001842:Bone and Bones / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000235:genetics; D006023:Glycoproteins / Q000096:biosynthesis / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009196:Myeloproliferative Disorders / Q000150:complications / Q000235:genetics; D010010:Osteoclasts / Q000473:pathology*; D010024:Osteoporosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053244:Osteoprotegerin; D010026:Osteosclerosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055728:Primary Myelofibrosis / Q000209:etiology; D011828:Radiation Chimera; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012190:Retroviridae / Q000235:genetics; D013926:Thrombopoietin / Q000235:genetics / Q000502:physiology*; D014161:Transduction, Genetic; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D053773:Transforming Growth Factor beta1
chemical_list: D006023:Glycoproteins; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C508961:Tgfb1 protein, mouse; C506031:Tnfrsf11b protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D013926:Thrombopoietin