IL-10 suppresses calcium-mediated costimulation of receptor activator NF-κB signaling during human osteoclast differentiation by inhibiting TREM-2 expression Academic Article uri icon

Overview

MeSH Major

  • Calcium
  • Cell Differentiation
  • Growth Inhibitors
  • Interleukin-10
  • Osteoclasts
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Immunologic
  • Signal Transduction

abstract

  • Induction of effective osteoclastogenesis by RANK (receptor activator of NF-kappaB) requires costimulation by ITAM-coupled receptors. In humans, the TREM-2 (triggering receptor expressed on myeloid cells 2) ITAM-coupled receptor plays a key role in bone remodeling, as patients with TREM-2 mutations exhibit defective osteoclastogenesis and bone lesions. We have identified a new rapidly induced costimulatory pathway for RANK signaling that is dependent on TREM-2 and mediated by calcium signaling. TREM-2-dependent calcium signals are required for RANK-mediated activation of calcium/calmodulin-dependent protein kinase (CaMK)II and downstream MEK and ERK MAPKs that are important for osteoclastogenesis. IL-10 inhibited RANK-induced osteoclastogenesis and selectively inhibited calcium signaling downstream of RANK by inhibiting transcription of TREM-2. Down-regulation of TREM-2 expression resulted in diminished RANKL-induced activation of the CaMK-MEK-ERK pathway and decreased expression of the master regulator of osteoclastogenesis NFATc1. These findings provide a new mechanism of inhibition of human osteoclast differentiation. The results also yield insights into crosstalk between ITAM-coupled receptors and heterologous receptors such as RANK, and they identify a mechanism by which IL-10 can suppress cellular responses to TNFR family members.

publication date

  • August 15, 2009

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2742169

Digital Object Identifier (DOI)

  • 10.4049/jimmunol.0804165

PubMed ID

  • 19625651

Additional Document Info

start page

  • 2444

end page

  • 55

volume

  • 183

number

  • 4