title: Suppression of experimental arthritis through AMP-activated protein kinase activation and autophagy modulation.
abstract: Autophagy plays a central role in various disease processes. However, its contribution to inflammatory arthritides such as rheumatoid arthritis (RA) is unclear. We observed that autophagy is engaged in the K/BxN serum transfer model of RA but autophagic flux is severely impaired. Metformin is an anti-diabetic drug that has been shown to stimulate autophagy. Induction of autophagic flux, through metformin-mediated AMP-activated protein kinase (AMPK) activation and interruption of mammalian target of rapamycin (mTOR) signaling mitigated the inflammation in experimental arthritis. Further investigation into the effects of metformin suggest that the drug directly activates AMPK and dose-dependently suppressed the release of TNF-α, IL-6, and MCP-1 by macrophages while enhancing the release of IL-10in vitro. In vivo, metformin treatment significantly suppressed clinical arthritis and inflammatory cytokine production. Mechanistic studies suggest that metformin exerts its anti-inflammatory effects by correcting the impaired autophagic flux observed in the K/BxN arthritis model and suppressing NF-κB-mediated signaling through selective degradation of IκB kinase (IKK). These findings establish a central role for autophagy in inflammatory arthritis and argue that autophagy modulators such as metformin may represent potential therapeutic agents for the treatment of RA.
authors.affiliation: Department of Medicine, Division of Rheumatology, Washington University School of Medicine, Saint Louis, Missouri.
authors.forename: Huimin
authors.initials: H
authors.lastname: Yan
authors.forename: Hui-Fang
authors.initials: HF
authors.lastname: Zhou
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.forename: Christine T N
authors.initials: CT
authors.lastname: Pham
keywords: AMP-activated protein kinase (AMPK); Autophagy; inflammatory arthritis; mammalian target of rapamycin (mTOR); metformin