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Stimulation of Notch Signaling in Mouse Osteoclast Precursors
08:01

Stimulation of Notch Signaling in Mouse Osteoclast Precursors

Published on: February 28, 2017

Differential regulation of osteoclastogenesis by Notch2/Delta-like 1 and Notch1/Jagged1 axes

Chiyoko Sekine1, Akemi Koyanagi, Noriko Koyama

  • 1Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Tokyo, 113-8421, Japan. csekine@juntendo.ac.jp

Arthritis Research & Therapy
|March 7, 2012
PubMed
Abstract

Insights

Blocking Delta-like 1 (Dll1) inhibits osteoclastogenesis, while Jagged1 enhances it, offering new therapeutic targets for rheumatoid arthritis (RA) bone erosion.

Area of Science:

  • Immunology
  • Cell Biology
  • Rheumatology

Background:

  • Osteoclastogenesis is crucial in rheumatoid arthritis (RA) bone erosion.
  • Notch receptors are involved in osteoclast development.
  • Specific Notch ligands driving this process in RA remained unidentified.

Purpose of the Study:

  • To identify the specific Notch receptors and ligands involved in osteoclastogenesis.
  • To elucidate the distinct roles of Notch ligands in regulating osteoclast formation.
  • To explore potential therapeutic targets for RA-related bone erosion.

Main Methods:

  • Osteoclast precursors (mouse macrophages/human monocytes) were cultured with RANKL and M-CSF.
  • Osteoclast differentiation was assessed via TRAP staining.
  • In vivo studies utilized K/BxN serum-induced arthritis and ovariectomized mouse models treated with blocking antibodies or fusion proteins targeting Notch ligands (Dll1, Jagged1).

Main Results:

  • Blocking Delta-like 1 (Dll1) inhibited osteoclastogenesis, while Dll1-Fc enhanced it.
  • Blocking Jagged1 enhanced osteoclastogenesis, while Jagged1-Fc suppressed it.
  • Dll1 promoted osteoclastogenesis via Notch2, and Jagged1 suppressed it via Notch1. Dll1/Notch2 pathway dominance was observed. Dll1 blockade ameliorated arthritis and reduced bone loss in vivo.

Conclusions:

  • The Notch2/Dll1 and Notch1/Jagged1 signaling pathways differentially regulate osteoclastogenesis.
  • Targeting these specific Notch axes presents a novel therapeutic strategy for mitigating bone erosion in rheumatoid arthritis.

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