Exploring the role of Transferrin receptor 1 for iron uptake in bone

Introduction: Maintaining balanced iron levels is essential for health. Iron circulates in the body primarily bound to the transport molecule transferrin, ensuring a stable, non-reactive state, and facilitating its delivery to tissues. 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 hematopoietic tissues and skeletal muscle, it is dispensable for iron acquisition in hepatocytes or intestinal epithelial cells. Bone health also heavily relies on balanced iron levels, with both iron overload and deficiency contributing to increased fracture risk. In this study, we investigated the significance of Tfr1 for iron uptake and cellular function in osteoblasts and osteoclasts.

Methods: We examined the bone characteristics of mice with cell-specific Tfr1^fl/fl;Osx:Cre+ (osteoprogenitors) and Tfr1^fl/fl;LysM:Cre+ (osteoclast precursors) conditional knockout. Using µCT and histomorphometry, we assessed bone microarchitecture in the femur and fourth vertebral body (L4) in male and female mice at 12 weeks of age. Additionally, systemic bone turnover markers PINP and TRAcP5b were analyzed. To mimic postmenopausal osteoporosis, ovariectomy was performed on 10-week-old female mice. Moreover, bone marrow-derived cells from Tfr1^fl/fl;Osx:Cre+ and Tfr1^fl/fl;LysM:Cre+ mice were cultured in vitro and differentiated into osteoblasts or osteoclasts, respectively, to assess cellular iron status as well as cellular differentiation and function.

Results: Our findings indicate that specific deletion of Tfr1 in osteoprogenitors in males resulted in increased bone mass at the axial skeleton [L4 BV/TV: 1.2-fold; p<0.01] with decreased bone formation rate [2.2-fold; p<0.05] as well as decreased levels of serum bone turnover markers [PINP: 1.3-fold; p<0.01, TRAcP5b: 1.5-fold; p<0.01]. Similarly, an increased bone mass in the appendicular skeleton [femoral BV/TV: 1.5-fold; p<0.01] and a decrease in bone turnover markers was found in females. Despite increased bone mass resulting from Tfr1 deficiency in osteoprogenitors, it did not mitigate the loss of bone mass following ovariectomy. At the cellular level, Tfr1-deficient osteoblasts showed decreased protein levels of the iron storage protein ferritin [1.3-fold; p<0.05] but did not exhibit changes in the mRNA expression of Alpl, Col1a1 or Bglap nor in the mineralization capacity. Conversely, Tfr1 deficiency in osteoclast precursors did not alter the bone phenotype of male and female mice nor the differentiation or activity of osteoclasts ex vivo.

Discussion: Taken together, our study reveals that Tfr1 might be important for iron uptake in osteoblasts to maintain proper bone turnover. However, the deletion of Tfr1 in osteoclasts did not affect bone microarchitecture. These results highlight distinct strategies for iron acquisition employed by various cell types in order to maintain cellular iron homeostasis.

Keywords: Tfr1, Iron, Osteoblast, Osteoclast

Korrespondenzadresse: Vanessa Passin, Department of Medicine III & Center for Healthy Aging, Medical Faculty and University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Fetscher Str. 74, 01307 Dresden, Deutschland, E-Mail: [e-mail]

Publication History

Article published online:
13 March 2024