Iron uptake through the transferrin cycle is essential for osteoclast differentiation, and iron overload in a variety of hematologic diseases is associated with excessive bone resorption. However, the molecular mechanisms regulating cellular iron metabolism in osteoclasts remain largely unknown. In this report, we provide evidence that Steap4, a member of the six-transmembrane epithelial antigen of prostate (Steap) family proteins, is an endosomal ferrireductase with a critical role in cellular iron utilization in osteoclast lineage cells. Specifically, we show that Steap4 is the only Steap family protein that is up-regulated during osteoclast differentiation. Knocking down Steap4 expression in vitro by lentivi... More
Iron uptake through the transferrin cycle is essential for osteoclast differentiation, and iron overload in a variety of hematologic diseases is associated with excessive bone resorption. However, the molecular mechanisms regulating cellular iron metabolism in osteoclasts remain largely unknown. In this report, we provide evidence that Steap4, a member of the six-transmembrane epithelial antigen of prostate (Steap) family proteins, is an endosomal ferrireductase with a critical role in cellular iron utilization in osteoclast lineage cells. Specifically, we show that Steap4 is the only Steap family protein that is up-regulated during osteoclast differentiation. Knocking down Steap4 expression in vitro by lentivirus-mediated short hairpin RNAs inhibits osteoclast formation and decreases cellular ferrous iron, reactive oxidative species, and the activation of CREB, a critical transcription factor downstream of RANKL-induced calcium signaling. We conclude that Steap4, working in concert with transferrin/transferrin receptor pathway, promotes cellular iron uptake and utilization to cope with the increased iron demand during osteoclast development and function.
