Involvement of the TGF-β1 Derived from Megakaryocyte in the PEG-rHuMGDF-Induced Myelofibrosis and Bone Formation
Ide Youichi1), Yamanaka Eri1), Namiki Yasuko1), Iijima Rieko1),
Harada Katsuhiko1), Ishi Hiromi1), Kawahara Jun-ichi1), Doi Kunio2)
1) Pharmaceutical Development Laboratories, Kirin Brewery Co., Ltd.
2) Department of Veterinary Pathology, Faculty of Agriculture, The University of Tokyo
(Received 11-Oct-2001)
(Accepted 29-Dec-2001)
Abstract: Bone marrow fibrosis and new bone formation were induced by Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) injection in the rat. We investigated time course changes of megakaryocyte counts, circulating platelet counts, transforming growth factor-β1 (TGF-β1) levels in the bone marrow and those in platelet-poor plasma (PPP) when rats were injected with PEG-rHuMGDF at a dose of 0.1 mg/kg. Additionally, ultrastructural analysis of the circulating platelet and the bone marrow was performed by electron microscope. PEG-rHuMGDF injection daily for 5 days caused a megakaryocyte hyperplasia on days 5-7[after the commencement of the treatment], myelofibrosis on days 7-10, and new bone formation on days 8-15. TGF-β1 levels in the extracellular fluid of the marrow, megakaryocyte numbers, TGF-β1 levels in the PPP, and circulating platelet counts increased by PEG-rHuMGDF injection, and reached to the maximum level on days 7, 7, 8, and 10, respectively. Ultrastructural analysis showed that circulating platelets had no prominent morphological changes in the PEG-rHuMGDF-treated rats on day 8, compared with vehicle-treated rats. Additionally, there were many platelets or fragments of megakaryocyte around mesenchymal cells, and those fragments deposited in the newly formed bone on day 10. These data suggested that myelofibrosis and new bone formation were induced by the increase of TGF-β1 levels derived from bone marrow megakaryocytes.
Key words: megakaryocyte, TGF-β1, myelofibrosis, platelet, new bone formation
