Kakumitsu Haruko, Kamezaki Kenjirou, Shimoda Kazuya, Karube Kennosuke, Haro Takashi, Numata Akihiko, Shide Koutarou, Matsuda Tadashi, Oshima Kouichi, Harada Mine
The First Department of Internal Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Fukuoka 812-8582, Japan.
Leuk Res. 2005 Jul;29(7):761-9. doi: 10.1016/j.leukres.2004.12.009. Epub 2005 Mar 2.
Thrombopoietin (TPO) regulates megakaryocytopoiesis and platelet production in vivo and in vitro. Exogenous overexpression of TPO in vivo by viral-mediated gene transfer induced bone marrow (BM) fibrosis and osteosclerosis. On the other hand, transgenic mice (Tg) overexpressing TPO using a liver-specific apolipoprotein E (Apo-E) promoter did not exhibit myelofibrosis or osteosclerosis. These discrepancies in phenotype are not fully understood. Then we have investigated the consequences of long-term in vivo overexpression of TPO in a mouse model. Murine TPO Tg mice driven by the IgH promoter were generated. The number of platelets and neutrophils in peripheral blood, and the number of megakaryocytes and granulocytic immature cells in the BM was elevated, together with the number of progenitor cells for megakaryocyte and myeloid cells. TPO Tg mice demonstrated anemia but the number of progenitor cells for the erythrocyte was increased. TPO Tg mice developed myelofibrosis and osteosclerosis as they aged with extramedullary hematopoiesis in the spleen. As plasma transforming growth factors (TGF)-beta1 and osteoprotegerin (OPG) levels were higher in TPO Tg mice than in wild-type mice, the development of myelofibrosis and osteosclerosis depends on local TPO levels in BM and might be due to elevated TGF-beta1 and OPG.
血小板生成素（TPO）在体内和体外均调节巨核细胞生成和血小板产生。通过病毒介导的基因转移在体内外源性过表达TPO会诱导骨髓（BM）纤维化和骨硬化。另一方面，使用肝脏特异性载脂蛋白E（Apo-E）启动子过表达TPO的转基因小鼠（Tg）未表现出骨髓纤维化或骨硬化。这些表型差异尚未完全了解。然后我们在小鼠模型中研究了TPO长期体内过表达的后果。生成了由IgH启动子驱动的小鼠TPO Tg小鼠。外周血中的血小板和中性粒细胞数量，以及BM中的巨核细胞和粒细胞未成熟细胞数量均升高，同时巨核细胞和髓细胞的祖细胞数量也增加。TPO Tg小鼠表现出贫血，但红细胞祖细胞数量增加。TPO Tg小鼠随着年龄增长出现骨髓纤维化和骨硬化，并伴有脾脏髓外造血。由于TPO Tg小鼠的血浆转化生长因子（TGF）-β1和骨保护素（OPG）水平高于野生型小鼠，骨髓纤维化和骨硬化的发展取决于BM中的局部TPO水平，可能是由于TGF-β1和OPG升高所致。
