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NDT Advance Access published online on October 2, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn551
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


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

Sarah A. Browne and Donal Reddan

Division of Nephrology, Dept of Medicine, National University of Ireland (NUI), Galway, Ireland

Correspondence and offprint requests to: Donal Reddan, Unit 1, Merlin Park University Hospital, Galway, Ireland. Tel: +35-3-91-775510; Fax: +35-3-91-720151; E-mail: donal.reddan{at}westernnephrology.com

Keywords: anaemia of chronic disease; bone morphogenetic proteins; hepcidin; iron metabolism; soluble haemojuvelin



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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 1.8-fold 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].



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Anaemia of CKD shares several characteristics of the anaemia of chronic disease, which is an immune-driven disorder. Elements of this include blunted erythropoietin response by erythroid precursors, decreased red blood cell survival and a defect in iron absorption and macrophage iron retention, which interrupts iron delivery to the erythroid precursor cells. The lack of erythropoietin and the anti-proliferative effect of uraemic toxins also contribute [9–11]. Dysregulation of iron homeostasis occurs with increased uptake and retention of iron within the cells of the reticuloendothelial system, which limits iron availability for erythropoieisis.

Hepcidin's role in iron metabolism has been demonstrated in many animal models [12]. Hepcidin gene expression seems exquisitely sensitive to regulation. The investigation of hepcidin in various clinical conditions had initially been impeded by the lack of anti-hepcidin antibodies and suitable assays. However, the western blot densitometric assay and ELISA techniques have detected it in human serum [13]. The circulating peptide is also small enough to be filtered by the kidneys, and in animals and humans urinary measurement is possible [1,6,14,15].

Central observations regarding hepcidin's role in iron metabolism are that hepcidin knockout mice develop iron overload and constitutive overexpression of hepcidin in mice leads to severe iron deficiency anaemia at birth, slows dietary iron absorption and cycling through macrophages and results in iron restricted erythropoiesis and failure to respond to erythropoietin [4].

Overexpression of hepcidin inhibits the iron accumulation normally observed in HFE (haemochromatosis gene)-deficient mice and its injection leads to reduced iron levels and accumulation in the reticuloendothelial system [16–19].

A number of genes have been designated roles in iron homeostasis by the identification of genetic mutation in human diseases. Impaired hepcidin expression results from mutations in any of the four different gene types—transferrin receptor 2 (TFR2), haemochromatosis type 2 (HFE2), hepcidin antimicrobial peptide (HAMP) and haemochromatosis (HFE). Mutations in haemochromatosis type 2 (HFE2), which encodes the protein haemojuvelin (HJV), result in the absence of hepcidin and early onset of iron overload disease.

Multiple pathways are known to regulate expression of hepcidin and thus indirectly affect iron uptake and retention. Regulation of hepcidin expression appears to occur at the level of transcription in that IL6, IL-1 alpha and IL-1 beta [20] induce transcription of HAMP in hepatocytes [2]. Recent studies also demonstrate that the bone morphogenetic protein BMP/SMAD (cytokines in transforming growth factor-beta (TGF) (TGF-beta family) signalling cascade is important for the basal regulation of hepcidin transcription. Specifically, BMP binds to a complex of type 1/2 serine threonine receptors, which phosphorylates a SMAD proteinase, complexing with SMAD4 and modulating gene transcription. Mice with liver-specific inactivation of SMAD4 cannot synthesize hepcidin in response to inflammation or iron overload [7,8,21]

Babitt et al. have shown previously that HJV is a co-receptor for bone morphogenetic protein (BMP) signalling and has a key role in its regulation [7]. Membrane (m)-HJV acts a co-receptor for BMP whereas soluble (s)-HJV may downregulate hepcidin competitively, interfering with BMP signalling. The way in which the two isoforms of HJV are regulated appears to be unclear at this time [22,23]. s-HJV was recently shown to originate from furin cleavage at position 332–335 and this process is upregulated by both iron deficiency and hypoxia. The study of HJV mutants shows a dual function for them in both iron deficiency and overload such as in the pathogenesis of juvenile haemochromatosis [24–26].

BMP signalling positively regulates hepcidin expression in liver cells in vitro [7]. BMP receptor expression is selective for specific members of TGF-beta family, and in vitro hepatocytes secrete BMP.

This paper demonstrates that BMP-2 administration increases hepcidin expression and decreases serum iron levels in vivo. It also demonstrates that HJV.Fc binds BMPs and acts as a BMP antagonist, selectively inhibiting BMP induction of hepcidin expression in vitro and that administration of HJV.Fc decreases hepcidin expression, increases ferroportin expression, mobilizes splenic iron stores and increases serum iron levels in vivo.

What is in it for the practicing nephrologist?
Intravenous iron is required by almost all end-stage kidney disease (ESKD) patients to maintain iron stores and permit adequate erythropoiesis [27]. Current clinical practice guidelines [28] suggest that predialysis and peritoneal dialysis patients should have transferrin saturation (TSAT) >20% and ferritin >100 ng/ml and that haemodialysis patients should have TSAT >20% with ferritin >200 ng/ml. Potential safety concerns with the administration of intravenous iron include anaphylaxis and concerns that iron overload can lead to end-organ damage [29,30].

The guidelines recommend caution in administering IV iron in situations where the ferritin is >500 ng/ml and suggest that the patient's clinical status, haemoglobin, transferrin saturation and degree of erythropoietin responsiveness should be taken into account before iron is administered. The recommendation to consider withholding iron from patients with elevated ferritin has significant implications for a large portion of the ESKD population.

The DRIVE (Dialysis Patients’ Response to IV Iron with Elevated Ferritin) trial [27] suggested that it was efficacious to treat the subset of patients with high ferritin (500–1200 ng/ml), decreased transferrin saturation (<25%) and anaemia with ferrous gluconate at doses considered normal in patients without elevated ferritin (1 g of ferrous gluconate), but it may not have been a large enough trial to address potential safety concerns. Adherence to current guidelines has economic implications also as iron deficiency whether functional or otherwise is associated with erythropoietin hyporesponsiveness. This paper suggests a role for modulators of the BMP signalling pathway in treating disease of iron overload and anaemia of chronic disease by exploiting the critical role of this pathway in the expression of hepcidin [3,7,8]. There is a lack of current therapeutic options for patients with elevated ferritin and functional iron deficiency for the practicing clinician. Inflammatory erythropoietin hyporesponsiveness has been reported to be improved by a number of interventions, including the use of biocompatible membranes, ultrapure dialysate, transplant nephrectomy, ascorbic acid therapy [31], vitamin E supplementation and oxpentifylline administration [32].

This paper raises the potential for improving iron availability by inhibiting hepcidin expression and may lead to an alternative to further iron dosing. Obviously these are animal studies and this is early in the development of such potential therapeutic options. As always, there is a need for caution among patients with infections and or malignancy as a decreased serum iron is believed to contribute towards host defence against invading pathogens or tumour cells [33]. Hepcidin itself has antimicrobial properties of uncertain importance [33] and the full implications of interfering with its own actions have not yet been completely studied.



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Hepcidin is centrally involved in iron regulation, and the development of BMP signalling modulators that regulate hepcidin expression may provide useful therapeutic options for the treatment of iron disorders.

Conflict of interest statement. None declared.



   Notes
 
* Comment on: Babitt JL, Huang FW, Xia Y et al. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest 2007; 117: 1933–1939. Back



   References
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Received for publication: 15.11.07
Accepted in revised form: 8. 9.08


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