Project Details
Projekt
Defining the role of the iron-sensor Tfr2 in ossification processes
Applicant
Dr. Ulrike Baschant
Subject Area
Endocrinology, Diabetology, Metabolism
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 436298031
Heterotopic ossification (HO) is a process of bone formation in soft tissue. In the first funding period, we have identified that iron overload induced by high iron diet aggravates heterotopic bone formation in mice whereas iron-deficiency significantly reduced HO. Further, we found higher iron levels in heterotopic bone tissues from mice and in patients with advanced HO. Analyzing the early stages of HO revealed increased local inflammation in iron overloaded HO mice. Anti-inflammatory treatment with Dexamethasone or 4-octylitaconate effectively prevented the exacerbation of iron-induced aggravation of HO. We further found that iron regulators seem to be involved in the pathological process of HO formation as Tfr2-deficient mice show iron-independent effects on HO and as iron overloaded FpnC326S-mutant mice did not reveal increased HO. Tfr2 deficiency resulted in an elevated and more severe HO reflected by an increase of infiltrating pro-inflammatory cells in the early stages of HO. Based on these findings, we aim to unravel the underlying mechanisms of HO-induced aggravation of HO by evaluating reactive oxygen species production and metabolic changes in iron-induced aggravation of HO. We further aim to identify critical cell types accumulating iron and driving the process of HO formation. To determine the impact of intracellular iron dysbalance on HO, we will apply different Fpn mutant mice that are specifically intracellular iron depleted. To evaluate the intrinsic role of iron regulators in HO, we will subject different hemochromatosis mouse models within the consortium to HO and analyze the different stages of HO.
DFG Programme
Research Units
