EXPLORING THE ROLE OF TRANSFERRIN RECEPTOR 1 IN BONE HOMEOSTASIS

Vanessa PASSIN1, Maria G. LEDESMA-COLUNGA1, Lorenz C. HOFBAUER1, Martina RAUNER1

1Department of Medicine III & Center for Healthy Aging, Medical Faculty and University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany

Bone health relies on balanced iron levels, with both iron overload and deficiency contributing to increased fracture risk. However, the mechanisms of iron acquisition in bone cells remain largely unknown. In this study, we investigated the significance of transferrin receptor 1 (Tfr1) for the cellular function in osteoblasts and osteoclasts.

Twelve-week-old male and female Tfr1fl/fl;Osx:Cre+ (osteoblasts) and Tfr1fl/fl;LysM:Cre+ (osteoclasts) conditional knockout mice, along with their littermate controls, were used to assess bone microarchitecture as well as systemic bone turnover markers PINP and TRAcP5b (microCT, histomorphometry, ELISA). Bone marrow-derived cells from these mice were cultured in vitro to assess cellular iron status, differentiation, and function (qPCR, Alizarin Red S, TRAP staining, western blot).

Tfr1fl/fl;Osx:Cre+ males showed an increased BV/TV at the lumbar spine [1.2-fold; p<0.01] with a decreased bone formation rate [2.2-fold; p<0.05] and lower levels of serum bone turnover markers [PINP: 1.3-fold; p<0.01, TRAcP5b: 1.5-fold; p<0.01]. Similarly, females displayed a higher femoral BV/TV [1.5-fold; p<0.01]. Tfr1-deficient osteoblasts showed decreased ferritin protein levels [1.3-fold; p<0.05] but no changes in mRNA levels of osteoblast-specific genes nor in their mineralization capacity. Conversely, Tfr1 deficiency in osteoclast precursors did not alter the bone phenotype in mice nor the iron status and differentiation of osteoclasts ex vivo. 

Taken together, Tfr1 might be important for iron uptake in osteoblasts, ensuring proper bone turnover, while its deletion in osteoclasts has no impact on bone microarchitecture. These results emphasize diverse iron acquisition strategies used by various cell types to maintain cellular iron homeostasis.