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Jagged1 Acts as an RBP-J Target and Feedback Suppresses TNF-Mediated Inflammatory Osteoclastogenesis

Courtney Ng1, Yongli Qin1,2, Yuhan Xia1

  • 1Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY.

Journal of Immunology (Baltimore, Md. : 1950)
|September 27, 2023
PubMed

Insights

Tumor necrosis factor (TNF) drives bone loss in inflammatory diseases. We found Jagged1, a Notch ligand, restrains TNF-induced osteoclast formation, offering a potential therapeutic target for inflammatory bone loss.

Area of Science:

  • Immunology
  • Cell Biology
  • Rheumatology

Background:

  • Tumor necrosis factor (TNF) is implicated in inflammatory bone resorption in diseases like rheumatoid arthritis (RA).
  • The mechanisms inhibiting TNF-driven osteoclastogenesis, particularly macrophage differentiation into osteoclasts, are not fully understood.
  • RBP-J is a known inhibitor of TNF-mediated osteoclastogenesis.

Purpose of the Study:

  • To identify novel mechanisms that restrain TNF-induced osteoclastogenesis.
  • To investigate the role of the Notch pathway, specifically Jagged1, in regulating TNF-mediated bone resorption.
  • To explore Jagged1 as a potential therapeutic target for inflammatory bone loss.

Main Methods:

  • Investigated the relationship between TNF, RBP-J, and Jagged1 expression in osteoclast differentiation.
  • Utilized mouse models and human peripheral blood monocytes for experiments.
  • Assessed the effect of recombinant Jagged1 on inflammatory osteoclastogenesis.

Main Results:

  • Identified Jagged1 as a direct RBP-J target, induced by TNF.
  • Demonstrated that TNF-induced Jagged1 acts as a feedback inhibitor of TNF-mediated osteoclastogenesis.
  • Observed decreased Jagged1 levels in RA patients, correlating with increased osteoclast formation.
  • Recombinant Jagged1 suppressed human inflammatory osteoclastogenesis without affecting inflammatory gene expression.

Conclusions:

  • Jagged1 links TNF and Notch signaling, acting as a crucial negative regulator of TNF-induced osteoclastogenesis.
  • Reduced Jagged1 levels in RA may contribute to excessive bone resorption.
  • Jagged1 represents a promising therapeutic target for mitigating inflammatory bone loss with minimal impact on the immune response.

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