A time kinetic study of the effect of aminobisphosphonate on murine haemopoiesis

We previously showed that aminobisphosphonates (aminoBPs), potent inhibitor s of bone resorption, increased the number of osteoclasts and granulocytes, and enhanced the cell size of osteoclasts in vivo, indicating that aminoBP s have a profound effect on murine haemopoiesis. The possible effect of an aminoBP (4-amino-1-hydroxybutylidene-1,1-bisphosphonate; AHBuBP) on murine haemopoiesis in vivo was examined in more detail. Macroscopically, AHBuBP i nduced the whitened bone marrow (BM) and splenomegaly. Flow cytometric anal ysis indicated that in BM, AHBuBP reduced the number of mature monocyte-mac rophage lineage cells and erythroid cells 1 and 2 d after treatment, respec tively, whereas it enhanced granulopoiesis on day 4. In the spleen, both er ythropoiesis and granulopoiesis were significantly increased. BM haemopoiet ic progenitors of granulocyte lineage and of monocyte-macrophage lineage (C FU-G, CFU-M and CFU-GM) were well maintained by the injection of AHBuBP, an d even a small increment in these progenitors was observed 2-4 d after trea tment. Immunohistochemical examination of BM demonstrated that residential macrophages of erythroblast ic islands disappeared. Increased numbers of os teoclasts, as well as enlarged cell size, was confirmed up to 7 d after the treatment, implicating that the inhibition of bone resorption was not due to the reduced generation of osteoclasts by AHBuBP. These results suggest ( 1) that AHBuBP treatment in vivo rapidly deleted mature residential macroph ages from BM, (2) that mature macrophages once deleted did not reappear eve n when CFU-M and CFU-GM increased in number and the number of Mac-1(+)/Gr-1 (-) cells recovered to normal, (3) that BM erythropoiesis was significantly decreased due to the lack of erythroblastic islands, and (4) that compensa tory erythropoiesis was evoked in the spleen to induce splenomegaly.