Project Details
Projekt
Deconstructing cell metabolic pathways causing iron toxicity-induced inhibition of osteoblast function, induction of FGF-23, and osteomalacia
Applicant
Professorin Dr. Martina Rauner
Subject Area
Endocrinology, Diabetology, Metabolism
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 436298031
Iron overload causes bone loss with increased bone resorption and decreased bone formation. Even though inhibited osteoblast function is a frequently reported observation in iron-induced bone loss, the mechanisms driving osteoblast inhibition beyond the induction of oxidative stress and ferroptosis are poorly understood. In the first funding period, we showed that loading bone cells with transferrin-bound iron is not detrimental for their differentiation and function. In line, knock-down of TFR1 did not impact bone cell function in vitro or in vivo, suggesting that other forms of iron such as non-transferrin bound iron have a negative impact on bone. In fact, treatment of osteoblasts with ferric ammonium citrate (FAC) profoundly decreased their differentiation, increased ROS production and lipid peroxidation. Metabolically, we found that FAC increased glycolysis and upregulated the expression of several enzymes necessary for the formation of lipids. Moreover, the anti-inflammatory and anti-oxidant metabolite itaconate was decreased after FAC treatment in osteoblasts in vitro and in the serum and bone of iron-treated mice. While iron treatment of mice led to an induction of FGF-23 levels and osteoid formation, an inhibition of bone formation, and a decrease in bone strength, treatment with the itaconate analog 4-octyl-itaconate (4OI) fully rescued all those parameters. 4OI treatment also fully rescued the iron-induced increase in lipid peroxidation in osteoblasts in vitro. As itaconate is a glycolysis inhibitor and rescued both, increased lipid peroxidation and FGF-23 levels, we hypothesize that iron metabolically reprograms osteoblasts to increase glycolysis to a) increase lipid peroxidation via stimulating the synthesis of lipids that are vulnerable to peroxidation and b) to induce FGF-23 levels and subsequent osteomalacia. We will test this hypothesis by treating osteoblasts and mice with iron with or without glycolysis inhibitors. Our main readouts will be oxidative stress and lipid analyses (peroxidation, lipid droplet formation, the lipidome profile), as well as FGF-23 levels and osteoid measurements. Moreover, besides inhibiting glycolysis, we plan to block enzymes critical for feeding into the lipid synthesis pathway. In summary, this project will help understand how iron affects osteoblast function and low bone mineralization and may provide novel metabolic targets to prevent osteoblast insufficiency during iron overload conditions.
DFG Programme
Research Units
