Peroxidase enzymes inhibit osteoclast differentiation and bone resorption

Vasilios Panagopoulos, Vasilios Liapis, Irene Zinonos, Shelley Hay, Damien A. Leach, Wendy Ingman, Mark O. DeNichilo, Gerald J. Atkins, David M. Findlay, Andrew C W Zannettino, Andreas Evdokiou

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

Myeloperoxidase (MPO) and eosinophil peroxidase (EPO) are heme-containing enzymes, well known for their antimicrobial activity, are released in abundance by innate immune infiltrates at sites of inflammation and injury. We have discovered new and previously unrecognised roles for heme peroxidases in extracellular matrix biosynthesis, angiogenesis, and bone mineralisation, all of which play an essential role in skeletal integrity. In this study we used in vitro models of osteoclastogenesis to investigate the effects of heme peroxidase enzymes on osteoclast differentiation and bone resorbing activity, pertinent to skeletal development and remodelling. Receptor activator of nuclear factor kappa B-ligand (RANKL) stimulates the formation of tartate-resistant acid phosphatase (TRAP) positive multinucleated cells and increases bone resorption when cultured with human peripheral blood mononuclear cells (PBMCs) or the RAW264.7 murine monocytic cell line. When RANKL was added in combination with either MPO or EPO, a dose-dependent inhibition of osteoclast differentiation and bone resorption was observed. Notably, peroxidases had no effect on the bone resorbing activity of mature osteoclasts, suggesting that the inhibitory effect of the peroxidases was limited to osteoclast precursor cells. Mechanistically, we observed that osteoclast precursor cells readily internalize peroxidases, and inhibited the phosphorylation of JNK, p38 MAPK and ERK1/2, important signalling molecules central to osteoclastogenesis. Our findings suggest that peroxidase enzymes, like MPO and EPO, may play a fundamental role in inhibiting RANKL-induced osteoclast differentiation at inflammatory sites of bone fracture and injury. Therefore, peroxidase enzymes could be considered as potential therapeutic agents to treat osteolytic bone disease and aberrant bone resorption.

Original languageEnglish
Pages (from-to)8-15
Number of pages8
JournalMolecular and Cellular Endocrinology
Volume440
DOIs
Publication statusPublished or Issued - 15 Jan 2017

Keywords

  • Eosinophil peroxidase
  • Myeloperoxidase
  • Osteoclast
  • Resorption

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology

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