High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin.
In thalassemia, deficient globin-chain production during erythropoiesis results in anemia. Thalassemia may be further complicated by iron overload (frequently exacerbated by blood transfusion), which induces numerous endocrine diseases, hepatic cirrhosis, cardiac failure and even death. Accumulation of iron in the absence of blood transfusions may result from inappropriate suppression of the iron-regulating peptide hepcidin by an erythropoietic mechanism. To test this hypothesis, we examined erythroblast transcriptome profiles from 15 healthy, nonthalassemic donors. Growth differentiation factor 15 (GDF15), a member of the transforming growth factor-beta superfamily, showed increased expression and secretion during erythroblast maturation. Healthy volunteers had mean GDF15 serum concentrations of 450 +/- 50 pg/ml. In comparison, individuals with beta-thalassemia syndromes had elevated GDF15 serum levels (mean 66,000 +/- 9,600 pg/ml; range 4,800-248,000 pg/ml; P < 0.05) that were positively correlated with the levels of soluble transferrin receptor, erythropoietin and ferritin. Serum from thalassemia patients suppressed hepcidin mRNA expression in primary human hepatocytes, and depletion of GDF15 reversed hepcidin suppression. These results suggest that GDF15 overexpression arising from an expanded erythroid compartment contributes to iron overload in thalassemia syndromes by inhibiting hepcidin expression.
Tanno
Toshihiko
T
Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
Bhanu
Natarajan V
NV
Oneal
Patricia A
PA
Goh
Sung-Ho
SH
Staker
Pamela
P
Lee
Y Terry
YT
Moroney
John W
JW
Reed
Christopher H
CH
Luban
Naomi L C
NL
Wang
Rui-Hong
RH
Eling
Thomas E
TE
Childs
Richard
R
Ganz
Tomas
T
Leitman
Susan F
SF
Fucharoen
Suthat
S
Miller
Jeffery L
JL
D023181:Antimicrobial Cationic Peptides / Q000235:genetics*; D016207:Cytokines / Q000097:blood*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055436:Growth Differentiation Factor 15; D064451:Hepcidins; D006801:Humans; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D012016:Reference Values; D013789:Thalassemia / Q000097:blood* / Q000235:genetics*; D014158:Transcription, Genetic
D023181:Antimicrobial Cationic Peptides; D016207:Cytokines; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; C578702:HAMP protein, human; D064451:Hepcidins; D012333:RNA, Messenger