Cell-autonomous osteoclast iron deficiency leads to osteopenia
Maintaining optimal bone health requires a proper balance of iron levels. Conditions characterized by excessive iron, such as hereditary hemochromatosis, often lead to complications such as osteoporotic fragility fractures. However, it remains unclear whether impaired bone remodeling arises from direct variations in bone iron content or alterations in the iron status of other organs. In this study, we generated a mouse model with iron deficiency specifically in myeloid-derived cells, including osteoclasts (FPNC326SLysMCre+), due to the presence of the Fpn p.C326S gain of function mutation in the iron exporter Ferroportin (Fpn).
FPNC326SLysMCre+ mice maintain balanced hepatic and systemic iron levels despite a reduction in splenic iron content. Bone analysis revealed severe iron deficiency, with significant architectural change: a decrease in trabecular volume and thickness and an increase in trabecular space. Additionally, it was observed an increased number of osteoclasts per total bone perimeter, without alterations in bone formation rate per bone surface.
Ex-vivo osteoclast cell culture assays demonstrated that osteoclasts derived from FPNC326S mice display increased bone resorption capacity without alterations in osteoclast formation. A similar phenotype was observed in wild-type osteoclasts treated with the iron chelator DFO, indicating that the phenotype may arise from intracellular iron deficiency.
In summary, our findings demonstrate that osteoclastic iron deficiency, even in the presence of balanced systemic iron levels, is sufficient to trigger significant alterations in bone microarchitecture due to increased osteoclast activity. This work holds promising translational implications, suggesting that modulating iron levels could serve as an adjunct to available antiresorptive therapies.
FPNC326SLysMCre+ mice maintain balanced hepatic and systemic iron levels despite a reduction in splenic iron content. Bone analysis revealed severe iron deficiency, with significant architectural change: a decrease in trabecular volume and thickness and an increase in trabecular space. Additionally, it was observed an increased number of osteoclasts per total bone perimeter, without alterations in bone formation rate per bone surface.
Ex-vivo osteoclast cell culture assays demonstrated that osteoclasts derived from FPNC326S mice display increased bone resorption capacity without alterations in osteoclast formation. A similar phenotype was observed in wild-type osteoclasts treated with the iron chelator DFO, indicating that the phenotype may arise from intracellular iron deficiency.
In summary, our findings demonstrate that osteoclastic iron deficiency, even in the presence of balanced systemic iron levels, is sufficient to trigger significant alterations in bone microarchitecture due to increased osteoclast activity. This work holds promising translational implications, suggesting that modulating iron levels could serve as an adjunct to available antiresorptive therapies.