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.
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Authors | Hédia Chagraoui, Micheline Tulliez, Tarek Smayra, Emiko Komura, Stéphane Giraudier, Theodore Yun, Nathalie Lassau, William Vainchenker, Françoise Wendling |
Journal | Blood
(Blood)
Vol. 101
Issue 8
Pg. 2983-9
(Apr 15 2003)
ISSN: 0006-4971 [Print] United States |
PMID | 12506018
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Glycoproteins
- Osteoprotegerin
- Receptors, Cytoplasmic and Nuclear
- Receptors, Tumor Necrosis Factor
- Recombinant Fusion Proteins
- Tgfb1 protein, mouse
- Tnfrsf11b protein, mouse
- Transforming Growth Factor beta
- Transforming Growth Factor beta1
- Thrombopoietin
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Topics |
- Animals
- Bone Marrow Transplantation
- Bone and Bones
(pathology)
- Cells, Cultured
- Disease Models, Animal
- Gene Expression Regulation
- Genetic Vectors
(genetics)
- Glycoproteins
(biosynthesis, blood, deficiency, genetics, physiology)
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Myeloproliferative Disorders
(complications, genetics)
- Osteoclasts
(pathology)
- Osteoporosis
(etiology, genetics, metabolism, pathology)
- Osteoprotegerin
- Osteosclerosis
(etiology, genetics, metabolism, pathology)
- Primary Myelofibrosis
(etiology)
- Radiation Chimera
- Receptors, Cytoplasmic and Nuclear
(biosynthesis, blood, deficiency, genetics, physiology)
- Receptors, Tumor Necrosis Factor
- Recombinant Fusion Proteins
(physiology)
- Retroviridae
(genetics)
- Thrombopoietin
(genetics, physiology)
- Transduction, Genetic
- Transforming Growth Factor beta
(biosynthesis, genetics)
- Transforming Growth Factor beta1
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