Wnt5a is a key target for the pro-osteogenic effects of iron chelation on osteoblast progenitors

摘要: Iron overload due to hemochromatosis or chronic blood transfusions has been associated with the development of osteoporosis. However, impact changes in iron homeostasis on osteoblast functions and underlying mechanisms are poorly defined. Since Wnt signaling is a critical regulator bone remodeling, we aimed analyze effects deficiency function, further define role these processes. Therefore, marrow stromal cells were isolated from wild-type mice differentiated towards osteoblasts. Exposure dose-dependently attenuated differentiation terms mineralization osteogenic gene expression, whereas chelation deferoxamine promoted time- dose-dependent manner up 3-fold. Similar results obtained for human cells. To elucidate whether pro-osteogenic effect mediated via signaling, performed profiler array deferoxamine-treated Wnt5a was amongst most highly induced genes. Further analysis revealed induction being up-regulated 2-fold after 48 h at 50 μM deferoxamine. Pathway using specific inhibitors that utilized phosphatidylinositol-3-kinase nuclear factor activated T cell pathways induce expression. Finally, confirmed requirement deferoxamine-mediated osteoblast-promoting by analyzing matrix Wnt5a-deficient The promoting completely abolished Wnt5a−/− Thus, data demonstrate