Osteostatin Mitigates Gouty Arthritis through the Inhibition of Caspase-1 Activation and Upregulation of Nrf2 Expression

Int J Mol Sci. 2024 Feb 27;25(5):2752. doi: 10.3390/ijms25052752.

Abstract

Gouty arthritis results from monosodium urate (MSU) crystal deposition in joints, initiating (pro)-interleukin (IL)-1β maturation, inflammatory mediator release, and neutrophil infiltration, leading to joint swelling and pain. Parathyroid hormone-related protein (107-111) C-terminal peptide (osteostatin) has shown anti-inflammatory properties in osteoblasts and collagen-induced arthritis in mice, but its impact in gouty arthritis models remains unexplored. We investigated the effect of osteostatin on pyroptosis, inflammation, and oxidation in macrophages, as well as its role in the formation of calcium pyrophosphate dihydrate crystals and MSU-induced gouty arthritis in mice models. Osteostatin ameliorated pyroptosis induced by lipopolysaccharide and adenosine 5'-triphosphate (LPS + ATP) in mice peritoneal macrophages by reducing the expression of caspase-1, lactate dehydrogenase release, and IL-1β and IL-18 secretion. Additionally, IL-6 and tumor necrosis factor-α (TNF-α) were also decreased due to the reduced activation of the NF-κB pathway. Furthermore, osteostatin displayed antioxidant properties in LPS + ATP-stimulated macrophages, resulting in reduced production of mitochondrial and extracellular reactive oxygen species and enhanced Nrf2 translocation to the nuclei. In both models of gouty arthritis, osteostatin administration resulted in reduced pro-inflammatory cytokine production, decreased leukocyte migration, and reduced caspase-1 and NF-κB activation. These results highlight the potential of osteostatin as a therapeutic option for gouty arthritis.

Keywords: Nrf2; caspase-1; gouty arthritis; immune response; inflammation; osteostatin.

MeSH terms

  • Adenosine Triphosphate
  • Animals
  • Arthritis, Gouty* / drug therapy
  • Caspases / metabolism
  • Inflammation / metabolism
  • Lipopolysaccharides / adverse effects
  • Mice
  • NF-E2-Related Factor 2 / metabolism
  • NF-kappa B / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Parathyroid Hormone-Related Protein*
  • Peptide Fragments*
  • Up-Regulation
  • Uric Acid

Substances

  • parathyroid hormone-related protein (107-111)
  • NF-E2-Related Factor 2
  • NF-kappa B
  • Lipopolysaccharides
  • Uric Acid
  • Adenosine Triphosphate
  • Caspases
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Peptide Fragments
  • Parathyroid Hormone-Related Protein