Ethyl pyruvate ameliorates inflammatory arthritis in mice

Int Immunopharmacol. 2017 Nov;52:333-341. doi: 10.1016/j.intimp.2017.09.027. Epub 2017 Oct 6.

Abstract

Objectives: Ethyl pyruvate (EP) is the ethyl ester of pyruvate and has antioxidative and anti-inflammatory effects. This study aimed to evaluate the therapeutic effect of EP in inflammatory arthritis and to identify the underlying mechanisms.

Methods: Mice with collagen-induced arthritis (CIA) were treated with the vehicle control or EP at 20mg/kg, and clinical and histological analyses were performed on the animals. The differentiation of murine CD4+ T cells into T helper 17 (Th17) cells in the presence of EP was investigated in vitro. The effects of EP on osteoclastogenesis were determined by staining for tartrate-resistant acid phosphatase, and measuring the mRNA levels of osteoclastogenesis-related genes. The expression of high-mobility group box 1 (HMGB1) was evaluated after EP therapy using immunohistochemical staining and Western blotting.

Results: EP significantly improved the clinical and histological features of arthritis in CIA mice. EP suppressed the differentiation of CD4+ T cells into Th17 cells, and inhibited the expression of RORγt. The generation of osteoclasts and osteoclastogenic markers from murine and human monocytes was significantly reduced in the presence of EP. The expression of HMGB1 in the synovium was significantly lower in CIA mice treated with EP, compared to control CIA mice. During osteoclastogenesis, HMGB1 release from monocytes was inhibited in the presence of EP.

Conclusions: EP attenuated synovial inflammation and bone destruction in the experimental arthritis model through suppression of IL-17 and HMGB-1. The data suggests that EP could be a novel therapeutic agent for the treatment of inflammatory arthritis, such as rheumatoid arthritis.

Keywords: Ethyl pyruvate; HMGB1; Pyruvate; Rheumatoid arthritis; T helper 17 cells.

MeSH terms

  • Animals
  • Arthritis, Experimental / drug therapy*
  • Arthritis, Rheumatoid / drug therapy*
  • Cell Differentiation
  • Cells, Cultured
  • Disease Models, Animal
  • HMGB1 Protein / metabolism
  • Humans
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Inbred DBA
  • Monocytes / physiology*
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Osteogenesis
  • Pyruvates / therapeutic use*
  • Synovial Membrane / metabolism
  • Th17 Cells / immunology*

Substances

  • HMGB1 Protein
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Pyruvates
  • ethyl pyruvate