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An Adoptive Transfer Model of Rheumatoid Arthritis in Mice
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An Adoptive Transfer Model of Rheumatoid Arthritis in Mice

Published on: June 6, 2025

Gadd45beta deficiency in rheumatoid arthritis: enhanced synovitis through JNK signaling

Camilla I Svensson1, Tomoyuki Inoue, Deepa Hammaker

  • 1University of California San Diego School of Medicine, La Jolla, CA 92093, USA.

Arthritis and Rheumatism
|October 31, 2009
PubMed
Abstract

Insights

Low Gadd45beta expression in rheumatoid arthritis (RA) worsens JNK activation and joint destruction. Enhancing Gadd45beta or inhibiting JNK may mitigate RA severity and joint damage.

Area of Science:

  • Rheumatology
  • Molecular Biology
  • Immunology

Background:

  • JNK signaling is crucial for matrix metalloproteinase (MMP) expression and joint destruction in rheumatoid arthritis (RA).
  • Gadd45beta, an NF-kappaB-regulated gene, negatively regulates the JNK pathway by inhibiting MKK-7.
  • Low Gadd45beta expression may enhance JNK activation and MMP production in RA.

Purpose of the Study:

  • To investigate if low Gadd45beta expression in RA enhances JNK activation and MMP overproduction.
  • To determine if Gadd45beta deficiency increases arthritis severity in a murine model.

Main Methods:

  • Analyzed NF-kappaB and JNK pathways and Gadd45beta expression in human RA synovium and fibroblast-like synoviocytes (FLS) using molecular biology techniques.
  • Evaluated Gadd45beta(-/-) and wild-type mice in the K/BxN serum transfer model of inflammatory arthritis, assessing clinical signs, osteoclast formation, and bone erosion.

Main Results:

  • Human RA synovium showed low Gadd45beta expression despite high NF-kappaB activity.
  • Forced Gadd45beta expression in FLS reduced JNK signaling, AP-1 activation, and MMP gene expression.
  • Gadd45beta deficiency worsened K/BxN arthritis, increased JNK signaling, elevated MMP3/MMP13 expression, and augmented synovial inflammation and osteoclast formation in mice.

Conclusions:

  • Deficient Gadd45beta expression in RA contributes to JNK activation, clinical arthritis exacerbation, and joint destruction.
  • Therapeutic strategies could involve enhancing Gadd45beta expression or inhibiting JNK/MKK-7 activity to mitigate RA progression.

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