The role of transforming growth factor-beta in PEG-rHuMGDF-induced reversible myelofibrosis in rats.
Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) injected at a suprapharmacologic dose (100 microg/kg) daily for 5 d in normal rats caused marked increases in marrow megakaryocytes and platelet counts at 6-8 d followed by gradual decreases to control levels at 10-20 d. Interestingly, in addition to the expected thrombopoiesis, PEG-rHuMGDF was associated with myelofibrosis with a predominance of reticulin fibres at day 10 followed by complete normalization by day 20. At 6-8 d, the levels of transforming growth factor-beta1 (TGF-beta1) in the extracellular fluid of the marrow, the platelet poor plasma, and the platelet extract were increased 23-, 7- and 2-fold, respectively. The elevated levels of TGF-beta1 were gradually reduced to baseline levels at 13-20 d in accordance with the normalization of myelofibrosis and thrombopoiesis. An ultrastructural analysis showed that large fragments of megakaryocytes were deposited in the marrow parenchyma of PEG-rHuMGDF-treated rats at day 6. PEG-rHuMGDF administration at pharmacologic doses (1 and 10 microg/kg) did not induce the deposition of reticulin fibres in the marrow. These findings suggest that TGF-beta1 leaked from megakaryocytes is involved in the development of the PEG-rHuMGDF-induced myelofibrosis and that this is a reversible process related to the regulation of the excess production of platelets.
Yanagida
M
M
Pharmaceutical Development Laboratory, Kirin Brewery Co. Ltd, Gunma, Japan.
Ide
Y
Y
Imai
A
A
Toriyama
M
M
Aoki
T
T
Harada
K
K
Izumi
H
H
Uzumaki
H
H
Kusaka
M
M
Tokiwa
T
T
D000818:Animals; D001853:Bone Marrow / Q000648:ultrastructure; D008297:Male; D008533:Megakaryocytes / Q000648:ultrastructure; D055728:Primary Myelofibrosis / Q000209:etiology*; D051381:Rats; D011994:Recombinant Proteins; D013922:Thrombocytosis / Q000209:etiology; D013926:Thrombopoietin / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology*
D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D013926:Thrombopoietin