Stimulation of osteoprotegerin production is responsible for osteosclerosis in mice overexpressing TPO.
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.
Chagraoui
Hédia
H
IFR 54-INSERM U 362, Institut Gustave Roussy, Villejuif, France.
Tulliez
Micheline
M
Smayra
Tarek
T
Komura
Emiko
E
Giraudier
Stéphane
S
Yun
Theodore
T
Lassau
Nathalie
N
Vainchenker
William
W
Wendling
Françoise
F
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
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