The non-erythropoietic EPO analogue cibinetide inhibits osteoclastogenesis in vitro and increases bone mineral density in mice

Zamzam Awida, Almog Bachar, Hussam Saed, Anton Gorodov, Nathalie Ben-Califa, Maria Ibrahim, Albert Kolomansky, Jennifer Ana Iden, Liad Graniewitz Visacovsky, Tamar Liron, Sahar Hiram-Bab, Michael Brines, Yankel Gabet, Drorit Neumann

Research output: Contribution to journalArticlepeer-review

Abstract

The two erythropoietin (EPO) receptor forms mediate different cellular responses to erythropoietin. While hematopoiesis is mediated via the homodimeric EPO receptor (EPOR), tissue protection is conferred via a heteromer composed of EPOR and CD131. In the skeletal system, EPO stimulates osteoclast precursors and induces bone loss. However, the underlying molecular mechanisms are still elusive. Here, we evaluated the role of the heteromeric complex in bone metabolism in vivo and in vitro by using Cibinetide (CIB), a non-erythropoietic EPO analogue that exclusively binds the heteromeric receptor. CIB is administered either alone or in combination with EPO. One month of CIB treatment significantly increased the cortical (~5.8%) and trabecular (~5.2%) bone mineral density in C57BL/6J WT female mice. Similarly, administration of CIB for five consecutive days to female mice that concurrently received EPO on days one and four, reduced the number of osteoclast progenitors, defined by flow cytometry as Lin-CD11b-Ly6Chi CD115+, by 42.8% compared to treatment with EPO alone. In addition, CIB alone or in combination with EPO inhibited osteoclastogenesis in vitro. Our findings introduce CIB either as a stand-alone treatment, or in combination with EPO, as an appealing candidate for the treatment of the bone loss that accompanies EPO treatment.

Original languageEnglish
Article number55
JournalInternational Journal of Molecular Sciences
Volume23
Issue number1
DOIs
StatePublished - 1 Jan 2022

Keywords

  • Bone marrow derived macrophages (BMDM)
  • CD131
  • Cibinetide
  • EPOR
  • Erythropoietin
  • Osteoclasts

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