Defining the role of the iron-sensor Tfr2 in ossification processes

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Heterotopic ossification (HO) is a process of ossification at abnormal anatomical sites. It is a common severe medical complication in patients after total hip replacement and it is a hallmark of the rare disease, fibrodysplasia ossificans progressiva (FOP). HO develops through a process of endochondral ossification involving stages of inflammation, chondrogenesis and osteogenesis. Mechanistically, bone morphogenetic protein (BMP) signaling has been implicated in the pathogenesis of HO. The BMP pathway is also an important regulator of iron homeostasis and we have recently shown that the iron regulator transferrin receptor 2 (Tfr2) regulates bone formation via the BMP-p38-MAPK pathway. Based on our discovery that the extracellular domain of Tfr2 (Tfr2-ECD) can bind BMP ligands and can be used as a ligand-trap to reduce HO, we hypothesize that Tfr2 plays a crucial role in the development of HO. Therefore, we aim to define the regulation of Tfr2 and its source in the various phases of HO by analyzing the inflammatory as well as the chondrogenic and osteogenic stages of HO in WT and Tfr2-/--mice. Furthermore we will determine the role of iron and other iron regulators in HO in mice. Additionally, we aim to validate the expression of Tfr2 and other iron regulators in HO tissue from patients after hip replacement surgeries. To unravel the underlying mechanisms of Tfr2 and BMP downstream signaling in HO, we will subject conditional Tfr2-deficient mice as well as conditional mice specific for BMP signal transducers to HO. Moreover, we will define the BMP binding sites within the Tfr2-ECD and test the ability of shorter BMP-binding Tfr2-ECD fragments to block BMP-2-induced ossification in vivo. The project will provide novel insights into the impact of iron regulators on HO. Refining the ligand trap may provide a novel therapeutic approach to abrogate HO and ameliorate FOP.