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An Adoptive Transfer Model of Rheumatoid Arthritis in Mice
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FTO-mediated RNA m6A methylation regulates synovial aggression and inflammation in rheumatoid arthritis

Ruiru Li1, Yu Kuang1, Yuanyuan Niu2

  • 1Department of Rheumatology and Immunology, the First Affiliated Hospital, Sun Yat-sen University, No.58 Zhongshan Er Road, Guangzhou 510080, Guangdong Province, China.

Biochimica Et Biophysica Acta. Molecular Basis of Disease
|July 18, 2024
PubMed

Insights

Fat mass and obesity-associated protein (FTO) drives rheumatoid arthritis (RA) inflammation and joint damage by regulating N6-methyladenosine (m6A) modification. Inhibiting FTO reduces RA severity, suggesting FTO as a potential therapeutic target.

Area of Science:

  • Rheumatology
  • Molecular Biology
  • Epigenetics

Background:

  • Fibroblast-like synoviocytes (FLS) are key drivers of synovial inflammation and joint damage in rheumatoid arthritis (RA).
  • N6-methyladenosine (m6A) is a prevalent mRNA modification implicated in various diseases, but its role in RA pathogenesis is unclear.

Purpose of the Study:

  • To investigate the role of the m6A demethylase fat mass and obesity-associated protein (FTO) in rheumatoid arthritis.

Main Methods:

  • Assessed FTO expression in RA patient FLS and synovium.
  • Utilized FTO knockdown and the FTO inhibitor FB23-2 in RA FLS models.
  • Examined FTO's effect on ADAMTS15 mRNA stability and IGF2BP1 interaction.
  • Evaluated therapeutic efficacy in collagen-induced arthritis (CIA) mouse and rat models.

Main Results:

  • FTO expression was elevated in RA FLS and synovium.
  • FTO inhibition reduced RA FLS migration, invasion, and inflammatory responses.
  • FTO overexpression enhanced RA FLS migration, invasion, and inflammation.
  • FTO stabilized ADAMTS15 mRNA via an m6A-IGF2BP1-dependent mechanism.
  • FB23-2 treatment or FTO shRNA injection significantly ameliorated arthritis severity in CIA models.

Conclusions:

  • FTO-mediated m6A modification contributes significantly to joint inflammation and damage in RA.
  • FTO inhibition presents a promising therapeutic strategy for managing rheumatoid arthritis.
Keywords:
ADAMTS15FTOFibroblast-like synoviocytesInvasionMigrationRheumatoid arthritism(6)A modification

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