@article{Ulrike Baschant_Martina Rauner_Ekaterina Balaian_Heike Weidner_Antonella Roetto_Uwe Platzbecker_Lorenz C. Hofbauer_2016, place={Pavia, Italy}, title={Wnt5a is a key target for the pro-osteogenic effects of iron chelation on osteoblast progenitors}, volume={101}, url={https://haematologica.org/article/view/7906}, DOI={10.3324/haematol.2016.144808}, abstractNote={Iron overload due to hemochromatosis or chronic blood transfusions has been associated with the development of osteoporosis. However, the impact of changes in iron homeostasis on osteoblast functions and the underlying mechanisms are poorly defined. Since Wnt signaling is a critical regulator of bone remodeling, we aimed to analyze the effects of iron overload and iron deficiency on osteoblast function, and further define the role of Wnt signaling in these processes. Therefore, bone marrow stromal cells were isolated from wild-type mice and differentiated towards osteoblasts. Exposure of the cells to iron dose-dependently attenuated osteoblast differentiation in terms of mineralization and osteogenic gene expression, whereas iron chelation with deferoxamine promoted osteogenic differentiation in a time- and dose-dependent manner up to 3-fold. Similar results were obtained for human bone marrow stromal cells. To elucidate whether the pro-osteogenic effect of deferoxamine is mediated <em>via</em> Wnt signaling, we performed a Wnt profiler array of deferoxamine-treated osteoblasts. <em>Wnt5a</em> was amongst the most highly induced genes. Further analysis revealed a time- and dose-dependent induction of <em>Wnt5a</em> being up-regulated 2-fold after 48 h at 50 μM deferoxamine. Pathway analysis using specific inhibitors revealed that deferoxamine utilized the phosphatidylinositol-3-kinase and nuclear factor of activated T cell pathways to induce <em>Wnt5a</em> expression. Finally, we confirmed the requirement of <em>Wnt5a</em> in the deferoxamine-mediated osteoblast-promoting effects by analyzing the matrix mineralization of <em>Wnt5a</em>-deficient cells. The promoting effect of deferoxamine on matrix mineralization in wild-type cells was completely abolished in Wnt5a<sup>−/−</sup> cells. Thus, these data demonstrate that <em>Wnt5a</em&gt; is critical for the pro-osteogenic effects of iron chelation using deferoxamine.}, number={12}, journal={Haematologica}, author={Ulrike Baschant and Martina Rauner and Ekaterina Balaian and Heike Weidner and Antonella Roetto and Uwe Platzbecker and Lorenz C. Hofbauer}, year={2016}, month={Nov.}, pages={1499-1507} }