A model of myelofibrosis and osteosclerosis in mice induced by overexpressing thrombopoietin (mpl ligand): reversal of disease by bone marrow transplantation.
We have previously shown that mice induced to overexpress thrombopoietin (TPO) by retroviral-mediated gene transfer into bone marrow (BM) cells develop myelofibrosis and osteosclerosis. It was speculated that these effects were secondary to TPO, resulting from high levels of megakaryocytes and platelets. Also, it was proposed that these mice represent a model for myelofibrosis and osteosclerosis. In this report, we show that levels of both transforming growth factor-beta 1 and platelet-derived growth factor are increased twofold to fivefold in the platelet-poor plasma of TPO overexpressing mice compared with control mice. These data suggest that the increased megakaryocytes produce elevated levels of these cytokines that lead to the pathogenesis of disease. Further, we retransplanted TPO overexpressing mice, at 40 to 42 weeks after primary transplantation, with normal BM cells. After the secondary transplantation, megakaryocytes and platelets returned to normal levels and the myelofibrosis and osteosclerosis were completely corrected. These data extend our initial studies of the effects of overexpression of TPO and show the potential use of this model to explore the underlying cause of myelofibrosis and osteosclerosis and potential treatments for these diseases.
Yan
X Q
XQ
Department of Developmental Hematology, Amgen Inc, Thousand Oaks, CA 91320-1789, USA.
Lacey
D
D
Hill
D
D
Chen
Y
Y
Fletcher
F
F
Hawley
R G
RG
McNiece
I K
IK
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D016026:Bone Marrow Transplantation; D001842:Bone and Bones / Q000473:pathology; D002478:Cells, Cultured / Q000637:transplantation / Q000821:virology; D004195:Disease Models, Animal; D005260:Female; D015967:Gene Expression Regulation, Viral; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000821:virology; D008297:Male; D008533:Megakaryocytes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010026:Osteosclerosis / Q000235:genetics* / Q000628:therapy*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D055728:Primary Myelofibrosis / Q000235:genetics* / Q000628:therapy*; D011533:Proviruses / Q000235:genetics; D011828:Radiation Chimera; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012091:Repetitive Sequences, Nucleic Acid; D012190:Retroviridae / Q000235:genetics; D013154:Spleen / Q000473:pathology; D013926:Thrombopoietin / Q000096:biosynthesis / Q000235:genetics*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism
D010982:Platelet-Derived Growth Factor; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D013926:Thrombopoietin