PUBLICATION

Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation

Authors
Steinbicker, A.U., Sachidanandan, C., Vonner, A.J., Yusuf, R.Z., Deng, D.Y., Lai, C.S., Rauwerdink, K.M., Winn, J.C., Saez, B., Cook, C.M., Szekely, B.A., Roy, C.N., Seehra, J.S., Cuny, G.D., Scadden, D.T., Peterson, R.T., Bloch, K.D., and Yu, P.B.
ID
ZDB-PUB-110325-13
Date
2011
Source
Blood   117(18): 4915-23 (Journal)
Registered Authors
Sachidanandan, Chetana
Keywords
none
MeSH Terms
  • Signal Transduction/drug effects
  • Bone Morphogenetic Proteins/antagonists & inhibitors*
  • Carrier Proteins/pharmacology
  • Hep G2 Cells
  • Hepcidins
  • Humans
  • Pyrazoles/pharmacology
  • Animals
  • Turpentine/toxicity
  • Zebrafish
  • Antimicrobial Cationic Peptides/metabolism
  • Hematopoietic Stem Cells/drug effects
  • Recombinant Proteins/pharmacology
  • Bone Morphogenetic Protein Receptors, Type I/antagonists & inhibitors
  • Mice, Inbred C57BL
  • Interleukin-6/pharmacology
  • Mice
  • Inflammation/complications*
  • Pyrimidines/pharmacology
  • Zebrafish Proteins/metabolism
  • Anemia/etiology*
  • Anemia/prevention & control*
(all 22)
PubMed
21393479 Full text @ Blood
Abstract
Anemia of inflammation develops in settings of chronic inflammatory, infectious, or neoplastic disease. In this highly prevalent form of anemia, inflammatory cytokines, including interleukin-6 (IL-6), stimulate hepatic expression of hepcidin, which negatively regulates iron bioavailability by inactivating ferroportin. Hepcidin is transcriptionally regulated by IL-6 and bone morphogenetic protein (BMP) signaling. We hypothesized that inhibiting BMP signaling can reduce hepcidin expression and ameliorate hypoferremia and anemia associated with inflammation. In human hepatoma cells, IL-6 induced hepcidin expression, an effect which was inhibited by treatment with a BMP type I receptor inhibitor, LDN-193189, or BMP ligand antagonists, noggin or ALK3-Fc. In zebrafish, the induction of hepcidin expression by transgenic expression of IL-6 was also reduced by LDN-193189. In mice, treatment with IL-6 or turpentine increased hepcidin expression and reduced serum iron, effects which were inhibited by LDN-193189 or ALK3-Fc. Chronic turpentine treatment led to microcytic anemia, which was prevented by concurrent administration of LDN-193189 or attenuated when LDN-193189 was administered after anemia was established. Our studies support the concept that BMP and IL-6 act together to regulate iron homeostasis and suggest that inhibition of BMP signaling may be an effective strategy for the treatment of anemia of inflammation.
Genes / Markers
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
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Citation
Steinbicker, A.U., Sachidanandan, C., Vonner, A.J., Yusuf, R.Z., Deng, D.Y., Lai, C.S., Rauwerdink, K.M., Winn, J.C., Saez, B., Cook, C.M., Szekely, B.A., Roy, C.N., Seehra, J.S., Cuny, G.D., Scadden, D.T., Peterson, R.T., Bloch, K.D., and Yu, P.B. (2011) Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation. Blood. 117(18):4915-23.