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

Kyung Hyun Park-Min, Jong Dae Ji, Taras Antoniv, Alicia C. Reid, Randi B. Silver, Mary Beth Humphrey, Mary Nakamura, Lionel B. Ivashkiv

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Abstract

Induction of effective osteoclastogenesis by RANK (receptor activator of NF-κB) 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.

Original languageEnglish
Pages (from-to)2444-2455
Number of pages12
JournalJournal of Immunology
Volume183
Issue number4
DOIs
Publication statusPublished - 2009 Aug 15

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ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

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