title: Stimulated erythropoiesis with secondary iron loading leads to a decrease in hepcidin despite an increase in bone morphogenetic protein 6 expression.
abstract: The BMP/SMAD signalling pathway plays an important role in iron homeostasis, regulating hepcidin expression in response to body iron levels. However, the role of this pathway in the reduction in hepcidin associated with increased erythropoiesis (and secondary iron loading) is unclear. To investigate this, we established a mouse model of chronic stimulated erythropoiesis with secondary iron loading using the haemolytic agent phenylhydrazine. We then examined the expression of components of the BMP6/SMAD signalling pathway in these animals. We also examined this pathway in the Hbb(th3/+) mouse, a model of the iron loading anaemia β-thalassaemia intermedia. Increasing doses of phenylhydrazine led to a progressive increase in both liver iron levels and Bmp6 mRNA expression, but, in contrast, hepatic Hamp expression declined. The increase in Bmp6 expression was not associated with a corresponding change in the phosphorylation of hepatic SMAD1/5/8, indicating that stimulated erythropoiesis decreases the ability of BMP6 to alter SMAD phosphorylation. Increased erythropoiesis also reduces the capacity of phosphorylated SMAD (pSMAD) to induce hepcidin, as Hamp levels declined despite no changes in pSMAD1/5/8. Similar results were seen in Hbb(th3/+) mice. Thus the erythroid signal probably affects some components of BMP/SMAD signalling, but also may exert some independent effects.
authors.affiliation: Iron Metabolism Laboratory, Queensland Institute of Medical Research, Brisbane, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Frazer
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Wilkins
authors.forename: Deepak
authors.initials: D
authors.lastname: Darshan
authors.forename: Alison C
authors.initials: AC
authors.lastname: Badrick
authors.forename: Gordon D
authors.initials: GD
authors.lastname: McLaren
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Anderson
mesh_terms: D000743:Anemia, Hemolytic / Q000139:chemically induced / Q000378:metabolism; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D055418:Bone Morphogenetic Protein 6 / Q000378:metabolism*; D004195:Disease Models, Animal; D004920:Erythropoiesis / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D055436:Growth Differentiation Factor 15 / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects; D064451:Hepcidins; D019190:Iron Overload / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010659:Phenylhydrazines / Q000009:adverse effects / Q000494:pharmacology; D010766:Phosphorylation; D011990:Receptors, Transferrin / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism; D017086:beta-Thalassemia / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; D055418:Bone Morphogenetic Protein 6; D055436:Growth Differentiation Factor 15; C579599:Hamp protein, mouse; D064451:Hepcidins; D010659:Phenylhydrazines; D011990:Receptors, Transferrin; D051785:Smad Proteins; D014168:Transferrin; C030299:phenylhydrazine; D048049:Extracellular Signal-Regulated MAP Kinases