Abstract:We studied the time courses of the number of osteoclasts, the expression of osteoblast differentiation markers and TGF-β1 levels in the platelet-poor plasma (PPP) in order to clarify the mechanism of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF)-induced bone formation in the mouse. Mice received PEG-rHuMGDF subcutaneously at a suprapharmacological dose (1.0 mg/kg) daily for 5 days (Day of the first injection: Day 1). PEG-rHuMGDF caused a gradual increase of platelet count, with a maximum increase on day 9. Histological analysis showed an increase of reticulin fibers on the inner side of endosteum on day 9, partial osteoid formation on day 11, new and excessive bone formation on day 13. On day 9, at the early stage of reticulin fiber increase, the number of osteoclasts was decreased. On day 11, osteopontin (OPN) mRNA-expression, a marker of osteoblast production, was observed in the reticulin fiber and osteoid near the substantia of bone marrow, whereas OPN mRNA-expressing cells did not express bone Gla protein (BGP) mRNA, a marker of osteoblasts, indicating that the expression of OPN mRNA was induced earlier than that of BGP mRNA during the course of osteogenesis. Additionally, the level of TGF-β1 in the PPP was increased, with about 2.5-fold elevation compared with the vehicle-treated mice at day 9. These findings suggest that PEG-rHuMGDF causes increase of reticulin fibers and osteogenesis by stimulating osteoblast differentiation and inhibiting osteoclast differentiation via an increase of the TGF-β1 level in the bone marrow. (J T oxicol Pathol 2001; 14: 113-120)
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 PEGrHuMGDF-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. (J Toxicol Pathol 2002; 15: 31-38)
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