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 language | English |
|---|---|
| Pages (from-to) | 2444-2455 |
| Number of pages | 12 |
| Journal | Journal of Immunology |
| Volume | 183 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2009 Aug 15 |
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ASJC Scopus subject areas
- Immunology
- Medicine(all)
Cite this
IL-10 suppresses calcium-mediated costimulation of receptor activator NF-κB signaling during human osteoclast differentiation by inhibiting TREM-2 expression. / Park-Min, Kyung Hyun; Ji, Jong Dae; Antoniv, Taras; Reid, Alicia C.; Silver, Randi B.; Humphrey, Mary Beth; Nakamura, Mary; Ivashkiv, Lionel B.
In: Journal of Immunology, Vol. 183, No. 4, 15.08.2009, p. 2444-2455.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - IL-10 suppresses calcium-mediated costimulation of receptor activator NF-κB signaling during human osteoclast differentiation by inhibiting TREM-2 expression
AU - Park-Min, Kyung Hyun
AU - Ji, Jong Dae
AU - Antoniv, Taras
AU - Reid, Alicia C.
AU - Silver, Randi B.
AU - Humphrey, Mary Beth
AU - Nakamura, Mary
AU - Ivashkiv, Lionel B.
PY - 2009/8/15
Y1 - 2009/8/15
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.0804165
DO - 10.4049/jimmunol.0804165
M3 - Article
VL - 183
SP - 2444
EP - 2455
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 4
ER -