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Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis.

Suragani, Rajasekhar N V S, Cadena, Samuel M, Cawley, Sharon M, Sako, Dianne, Mitchell, Dianne, Li, Robert, Davies, Monique V, Alexander, Mark J, Devine, Matthew, Loveday, Kenneth S, Underwood, Kathryn W, Grinberg, Asya V, Quisel, John D, Chopra, Rajesh, Pearsall, R Scott, Seehra, Jasbir, Kumar, Ravindra·2014·Nature Medicine
DOI 10.1038/nm.3512
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Abstract

Erythropoietin (EPO) stimulates proliferation of early-stage erythrocyte precursors and is widely used for the treatment of chronic anemia. However, several types of EPO-resistant anemia are characterized by defects in late-stage erythropoiesis, which is EPO independent. Here we investigated regulation of erythropoiesis using a ligand-trapping fusion protein (ACE-536) containing the extracellular domain of human activin receptor type IIB (ActRIIB) modified to reduce activin binding. ACE-536, or its mouse version RAP-536, produced rapid and robust increases in erythrocyte numbers in multiple species under basal conditions and reduced or prevented anemia in murine models. Unlike EPO, RAP-536 promoted maturation of late-stage erythroid precursors in vivo. Cotreatment with ACE-536 and EPO produced a synergistic erythropoietic response. ACE-536 bound growth differentiation factor-11 (GDF11) and potently inhibited GDF11-mediated Smad2/3 signaling. GDF11 inhibited erythroid maturation in mice in vivo and ex vivo. Expression of GDF11 and ActRIIB in erythroid precursors decreased progressively with maturation, suggesting an inhibitory role for GDF11 in late-stage erythroid differentiation. RAP-536 treatment also reduced Smad2/3 activation, anemia, erythroid hyperplasia and ineffective erythropoiesis in a mouse model of myelodysplastic syndromes (MDS). These findings implicate transforming growth factor-β (TGF-β) superfamily signaling in erythroid maturation and identify ACE-536 as a n…

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  • Entire pathways such as MAPK are no longer hijacked for non-canonical induction of TGF-beta, Smad1, and inflammation but instead engage in productive signaling by their cognate ligands, promoting tissue health, regeneration, and homeostatic production of cytokines and growth factors.

    “entire pathways (MAPK, for example) are no longer hijacked for non-canonical induction of TGF-beta, Smad1, and inflammation [57, 58], but instead engage in productive signaling by their cognate ligands, promoting tissue health, regeneration and homeostatic production of cytokines and growth factors [59–61] (with their own positive feed-backs), as we observe.”

    From Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin (2020) · cites this paper as [59]

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Metadata

Authors
Suragani, R. N. V. S., Cadena, S. M., Cawley, S. M., Sako, D., Mitchell, D., Li, R., Davies, M. V., Alexander, M. J., Devine, M., Loveday, K. S., Underwood, K. W., Grinberg, A. V., Quisel, J. D., Chopra, R., Pearsall, R. S., Seehra, J., & Kumar, R.
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2014-03-23
Volume
20
Issue
4
Pages
408-414
ISSN
  • 1078-8956
  • 1546-170X
DOI
10.1038/nm.3512
Cited by
445
References
2
Language
en
Licence

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