TY - JOUR T1 - HIF-stabilization prevents delayed fracture healing JF - bioRxiv DO - 10.1101/2020.07.02.182832 SP - 2020.07.02.182832 AU - Annemarie Lang AU - Sarah Helfmeier AU - Jonathan Stefanowski AU - Aditi Kuppe AU - Vikram Sunkara AU - Moritz Pfeiffenberger AU - Angelique Wolter AU - Alexandra Damerau AU - Shabnam Hemmati-Sadeghi AU - Jochen Ringe AU - Rainer Haag AU - Anja E. Hauser AU - Max Löhning AU - Carsten Perka AU - Georg N. Duda AU - Paula Hoff AU - Katharina Schmidt-Bleek AU - Timo Gaber AU - Frank Buttgereit Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/07/03/2020.07.02.182832.abstract N2 - The initial phase of fracture healing decides on success of bone regeneration and is characterized by an inflammatory milieu and low oxygen tension (hypoxia). Negative interference with or prolongation of this fine-tuned initiation phase will ultimately lead to a delayed or incomplete healing such as non-unions which then requires an effective and gentle therapeutic intervention. Common reasons include a dysregulated immune response, immunosuppression or a failure in cellular adaptation to the inflammatory hypoxic milieu of the fracture gap and a reduction in vascularizing capacity by environmental noxious agents (e.g. rheumatoid arthritis, smoking). The hypoxia-inducible factor (HIF)-1α is responsible for the cellular adaptation to hypoxia, activating angiogenesis and supporting cell attraction and migration to the fracture gap. Here, we hypothesized that stabilizing HIF-1α could be a cost-effective and low-risk prevention strategy of fracture healing disorders. Therefore, we combined a well-known HIF-stabilizer – deferoxamine (DFO) – and a less known HIF-enhancer – macrophage migration inhibitory factor (MIF) – to synergistically induce improved fracture healing. Stabilization of HIF-1α enhanced calcification and osteogenic differentiation of MSCs in vitro. In vivo, the application of DFO with or without MIF during the initial healing phase accelerated callus mineralization and vessel formation in a clinically relevant mouse-osteotomy-model in a compromised healing setting. Our findings provide support for a promising preventive strategy towards bone healing disorders in patients with a higher risk due to e.g. delayed neovascularization by accelerating fracture healing using DFO and MIF to stabilize HIF-1α.Competing Interest StatementThe authors have declared no competing interest. ER -