Bone phenotype in male and female mice after knockdown of transferrin receptor 1 in osterix-expressing cells

Transferrin receptor 1 (Tfr1) plays a key role in mediating the cellular uptake of transferrin-bound iron. While Tfr1 is essential for iron uptake in erythroid cells and skeletal muscle, it is dispensable for iron acquisition in hepatocytes, intestinal epithelial, or endothelial cells. In this study, we investigated the significance of Tfr1 for iron uptake and cellular function in bone-forming osteoblasts. Therefore, we examined the bone characteristics of male and female Tfr1^fl/fl;Osx:cre^+/- (osteoprogenitors) conditional KO mice at 12 and 24 wk of age. Bone marrow-derived cells from Tfr1^fl/fl;Osx:cre^+/- mice were differentiated into osteoblasts in vitro to assess cellular iron status as well as cellular differentiation and function. Our findings indicate that Tfr1 deficiency in osteoprogenitors in male mice resulted in increased trabecular bone mass in the axial skeleton with decreased bone formation rate as well as decreased levels of serum bone turnover markers. Despite increased bone mass in the femur in females resulting from Tfr1 deficiency in osteoprogenitors, loss of bone mass following ovariectomy was not mitigated. Transferrin receptor 1-deficient osteoblasts showed mild changes in cytosolic iron levels and decreased mineralization. These results suggest a minor role of Tfr1 in osteoblasts differentiation and function but highlight distinct strategies for iron acquisition employed by bone cells to maintain cellular iron homeostasis.