Molecular Medicine

, Volume 20, Supplement 1, pp S10–S16 | Cite as

Discovery of a Master Regulator of Injury and Healing: Tipping the Outcome from Damage toward Repair

  • Michael Brines


Disease processes provoke a balancing act between tissue damage and repair. In the 1980s, the discovery that tumor necrosis factor (TNF)-α is a general mediator of disease-related injury led to the development of novel therapeutics to neutralize its activity. In contrast, identification of potential mediator(s) of tissue repair remained elusive. Studies performed over the last 15 years have documented that the type 1 cytokine erythropoietin (EPO), produced by cells within surrounding regions subjected to injury, acts as a master regulator, controlling both damage and repair. The transducer of these activities is the previously unrecognized innate repair receptor (IRR), which is comprised of the EPO receptor and β common receptor subunits. Notably, although proinflammatory cytokines upregulate the IRR, EPO and proinflammatory cytokines inhibit each other’s production, resulting in a relative underproduction of EPO. Although exogenous EPO attenuates disease activity in many preclinical models, its clinical utility is limited by serious hematopoietic and thrombotic adverse effects. To circumvent this problem, novel compounds engineered from the structure of EPO have been developed as selective ligands of the IRR. These compounds possess no hematopoietic activity, yet are fully tissue-protective and reparative. The lead molecule of this development effort (the 11-amino acid peptide ARA290) tips the balance toward healing in diverse preclinical models of disease and is currently under evaluation in advanced clinical trials as a disease-modifying agent in painful neuropathy and diabetes.



As can easily be observed by looking at the publications arising from this area of research over the years, I have been especially blessed by an abundance of collaborators of the highest caliber from around the world. Unfortunately, there are too many to mention here in the concern that I will inadvertently fail to acknowledge someone. It has always amazed me how many individuals take considerable time to meet and discuss topics that are often somewhat outside of their area of core expertise. Without this collegiate collaboration, this work could not have progressed as rapidly or as far as it has. I also sincerely thank the many volunteers and patients, as well as their families, for agreeing to participate in our clinical research programs.


  1. 1.
    Ehrenreich H, et al. (2004) Erythropoietin: a candidate compound for neuroprotection in schizophrenia. Mol. Psychiatry 9:42–54.CrossRefGoogle Scholar
  2. 2.
    Sakanaka M, et al. (1998) In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc. Natl. Acad. Sci U. S. A. 95:4635–4640.CrossRefGoogle Scholar
  3. 3.
    Brines ML, et al. (2000) Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc. Natl. Acad. Sci. U. S. A. 97:10526–31.CrossRefGoogle Scholar
  4. 4.
    Morishita E, Masuda S, Nagao M, Yasuda Y, Sasaki R. (1997) Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience. 76:105–16.CrossRefGoogle Scholar
  5. 5.
    Masuda S, et al. (1994) A novel site of erythropoietin production: oxygen-dependent production in cultured rat astrocytes. J. Biol. Chem. 269:19488–93.PubMedGoogle Scholar
  6. 6.
    Brines M, Cerami A. (2008) Erythropoietin-mediated tissue protection: reducing collateral damage from the primary injury response. J. Intern. Med. 264:405–32.CrossRefGoogle Scholar
  7. 7.
    Erbayraktar Z, et al. (2009) Nonerythropoietic tissue protective compounds are highly effective facilitators of wound healing. Mol. Med. 15:235–41.CrossRefGoogle Scholar
  8. 8.
    Kaneko N, Kako E, Sawamoto K. (2013) Enhancement of ventricular-subventricular zone-derived neurogenesis and oligodendrogenesis by erythropoietin and its derivatives. Front. Cell. Neurosci. 7:235.CrossRefGoogle Scholar
  9. 9.
    Viviani B, et al. (2005) Erythropoietin protects primary hippocampal neurons increasing the expression of brain-derived neurotrophic factor. J. Neurochem. 93:412–21.CrossRefGoogle Scholar
  10. 10.
    Erbayraktar S, et al. (2003) Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo. Proc. Natl. Acad. Sci. U. S. A. 100:6741–6.CrossRefGoogle Scholar
  11. 11.
    Masuda S, et al. (1993) Functional erythropoietin receptor of the cells with neural characteristics: comparison with receptor properties of erythroid cells. J. Biol. Chem. 268:11208–16.PubMedGoogle Scholar
  12. 12.
    Brines M, et al. (2004) Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc. Natl. Acad. Sci. U. S. A. 101:14907–12.CrossRefGoogle Scholar
  13. 13.
    Ehrenreich H, et al. (2002) Erythropoietin therapy for acute stroke is both safe and beneficial. Mol. Med. 8:495–505.CrossRefGoogle Scholar
  14. 14.
    Corwin HL, et al. (2007) Efficacy and safety of epoetin alfa in critically ill patients. N. Engl. J. Med. 357:965–76.CrossRefGoogle Scholar
  15. 15.
    Leist M, et al. (2004) Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science. 305:239–42.CrossRefGoogle Scholar
  16. 16.
    Brines M, Cerami A. (2012) The receptor that tames the innate immune response. Mol. Med. 18:486–96.CrossRefGoogle Scholar
  17. 17.
    Brines M, Cerami A. (2013) Erythropoietin and engineered innate repair activators. Methods Mol. Biol. 982:1–11.CrossRefGoogle Scholar
  18. 18.
    Brines M, et al. (2008) Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc. Natl. Acad. Sci. U. S. A. 105: 10925–30.CrossRefGoogle Scholar
  19. 19.
    Swartjes M, et al. (2011) ARA290, a peptide derived from the tertiary structure of erythropoietin, produces long-term relief of neuropathic pain: an experimental study in rats and beta-common receptor knockout mice. Anesthesiology. 115:1084–92.CrossRefGoogle Scholar
  20. 20.
    Swartjes M, et al. (2014) ARA 290, a peptide derived from the tertiary structure of erythropoietin, produces long-term relief of neuropathic pain coupled with suppression of the spinal microglia response. Mol. Pain. 10:13.CrossRefGoogle Scholar
  21. 21.
    Dahan A, et al. (2013) ARA 290 improves symptoms in patients with sarcoidosis-associated small nerve fiber loss and increases corneal nerve fiber density. Mol. Med. 19:334–45.CrossRefGoogle Scholar
  22. 22.
    Heij L, et al. (2012) Safety and efficacy of ARA 290 in sarcoidosis patients with symptoms of small fiber neuropathy: a randomized, doubleblind pilot study. Mol. Med. 18:1430–6.CrossRefGoogle Scholar
  23. 23.
    Schmidt RE, et al. (2011) Effect of insulin and an erythropoietin-derived peptide (ARA290) on established neuritic dystrophy and neuronopathy in Akita (Ins2 Akita) diabetic mouse sympathetic ganglia. Exp. Neurol. 232:126–35.CrossRefGoogle Scholar

Copyright information

© The Author(s) 2014

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (

Authors and Affiliations

  1. 1.Araim PharmaceuticalsTarrytownUSA

Personalised recommendations