Potential role of bone morphogenetic protein (BMP) signalling as a potential therapeutic target for modification of iron balance

Abstract

This important paper by Babitt et al. outlines a novel method of regulating hepcidin expression that could potentially lead to novel methods of improving iron utilization amongst patients with anaemia of chronic kidney disease (CKD). Hepcidin is the master regulator of systemic iron homeostasis acting by causing the internalization and degradation of the iron exporter channel, ferroportin. This blocks the efficient transfer of iron to plasma and therefore functionally blocks iron absorption [1,2,3]. Hepcidin also blocks the transfer of iron from the reticuloendothelial system to plasma in chronic inflammatory disease states [4]. Increased levels of hepcidin thus contribute to anaemia of inflammation by shunting iron away from erythropoiesis and sequestrating it in organs such as the liver and spleen [5]. Hepcidin deficiency itself can lead to haemochromatosis [6]. Babitt et al. outline a novel method of regulating hepcidin expression using BMP signalling. Hepcidin expression was initially increased by the injection of purified BMP-2 at a dose of 1 mg/kg. retroorbitally into mice, and 4 h postinjection, hepatic hepcidin mRNA levels increased 1.8fold and serum iron levels decreased. Subsequently, soluble haemojuvelin (HJV.Fc) a selective inhibitor of BMP induction of hepcidin expression in vitro decreases hepcidin expression, leading to increased ferroportin expression, mobilization of splenic iron stores and increased serum iron levels in vivo. This work further demonstrates the key role of hepcidin in iron haemostasis, supporting the pharmacological use of hepcidin agonists, and antagonists in various disorders of iron haemostasis [7,8].