ZNRF3 Regulates Collagen-Induced Arthritis Through NF-kB and Wnt Pathways

Inflammation. 2020 Jun;43(3):1077-1087. doi: 10.1007/s10753-020-01193-1.

Abstract

Although the E3 ubiquitin ligase Zinc and ring finger 3 (ZNRF3) negatively regulates the Wnt signaling pathway, its function in rheumatoid arthritis (RA) is elusive. Here, the effects and the mechanism of ZNRF3 on a mouse model of collagen-induced arthritis (CIA) and human fibroblast-like synoviocytes (FLS) obtained from RA patients were determined. Our results showed that ZNRF3 was highly expressed in tissues and FLSs compared to trauma patients. Lentivirus-mediated silencing of ZNRF3 induced apoptosis decreased cell viability and significantly attenuated inflammation in RA-FLSs via tumor necrosis-α (TNF-α). Additionally, silencing of ZNRF3 reduced knee joint damage and also decreased the level of TNF-α, IL-1β, and IL-6 in the CIA mouse model. These effects were mediated by the crosstalk between Wnt and NF-κB pathways in RA-FLS.

Keywords: NF-κB pathway; Wnt/β-catenin pathway; ZNRF3; collagen-induced arthritis; rheumatoid arthritis; synovial fibroblasts.

MeSH terms

  • Aged
  • Animals
  • Arthritis, Experimental / chemically induced
  • Arthritis, Experimental / genetics
  • Arthritis, Experimental / metabolism*
  • Collagen / toxicity
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred DBA
  • Middle Aged
  • NF-kappa B / metabolism*
  • Synoviocytes / drug effects
  • Synoviocytes / metabolism
  • Ubiquitin-Protein Ligases / antagonists & inhibitors
  • Ubiquitin-Protein Ligases / biosynthesis*
  • Ubiquitin-Protein Ligases / genetics
  • Wnt Signaling Pathway / drug effects
  • Wnt Signaling Pathway / physiology*

Substances

  • NF-kappa B
  • Collagen
  • Ubiquitin-Protein Ligases
  • Znrf3 protein, mouse