Thrombopoietin is a multifunctional factor

Thrombopoietin (TPO) is the critical regulator of proliferation and differentiation of megakaryocytic lineage. TPO has potent stimulatory effects on platelet production in patients with chemotherapy-induced thrombocytopenia. In addition to sustaining megakaryocytopoiesis, TPO may play an important role in regulating neutrophil activation and erythropoiesis. Furthermore, TPO induces proliferation of acute myeloblastic leukemia cells in vitro in some cases. These results suggest that TPO may be multifunctional factor. Recently osteosclerosis is observed in TPO transgenic mice. To determine whether TPO can modulate the osteoclastic differentiation from hematopoietic stem cells, we investigated the effect of TPO on in vitro osteogenesis. TPO inhibited the formation of osteoclastic cells and decreased the areas of bone resorption pits in a dose-dependent manner. We examined whether transforming growth factor-beta (TGF-beta) and platelet derived growth factor (PDGF), major cytokines produced by megakaryocytes, mediate the inhibitory effect of TPO. The addition of either anti-TGF-beta or anti-PDGF antibody to bone marrow cell cultures completely antagonized the effect of TPO on osteoclastogenesis. These data suggest that TPO inhibits osteoclastogenesis by stimulating thrombopoiesis and that TGF-beta and PDGF mediate the effect of TPO by impacting macrophage-lineage cells as osteoclast precursors.