title: Wnt5a is a key target for the pro-osteogenic effects of iron chelation on osteoblast progenitors.
abstract: 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 via Wnt signaling, we performed a Wnt profiler array of deferoxamine-treated osteoblasts. Wnt5a was amongst the most highly induced genes. Further analysis revealed a time- and dose-dependent induction of Wnt5a 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 Wnt5a expression. Finally, we confirmed the requirement of Wnt5a in the deferoxamine-mediated osteoblast-promoting effects by analyzing the matrix mineralization of Wnt5a-deficient cells. The promoting effect of deferoxamine on matrix mineralization in wild-type cells was completely abolished in Wnt5a-/-cells. Thus, these data demonstrate that Wnt5a is critical for the pro-osteogenic effects of iron chelation using deferoxamine.
authors.affiliation: Department of Medicine III, Technische Universität Dresden, Saxony, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Baschant
authors.affiliation: Department of Medicine III, Technische Universität Dresden, Saxony, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Rauner
authors.affiliation: Department of Medicine I, Technische Universität Dresden, Saxony, Germany.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Balaian
authors.affiliation: Department of Medicine I, Technische Universität Dresden, Saxony, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Weidner
authors.affiliation: Department of Clinical and Biological Science, University of Torino, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Roetto
authors.affiliation: Department of Medicine I, Technische Universität Dresden, Saxony, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Platzbecker
authors.affiliation: Department of Medicine III, Technische Universität Dresden, Saxony, Germany lorenz.hofbauer@uniklinikum-dresden.de.|Center for Regenerative Therapies Dresden, Saxony, Germany.|Center for Healthy Aging, Technische Universität Dresden, Saxony, Germany.
authors.forename: Lorenz C
authors.initials: LC
authors.lastname: Hofbauer
mesh_terms: D000328:Adult; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003676:Deferoxamine / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D050778:NFATC Transcription Factors / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071818:Wnt-5a Protein / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D007502:Iron Chelating Agents; D050778:NFATC Transcription Factors; D000071818:Wnt-5a Protein; D007501:Iron; D019869:Phosphatidylinositol 3-Kinases; D003676:Deferoxamine