IL-10 suppresses calcium-mediated costimulation of receptor activator NF-kappa B signaling during human osteoclast differentiation by inhibiting TREM-2 expression.
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.
Park-Min
Kyung-Hyun
KH
Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA.
Ji
Jong-Dae
JD
Antoniv
Taras
T
Reid
Alicia C
AC
Silver
Randi B
RB
Humphrey
Mary Beth
MB
Nakamura
Mary
M
Ivashkiv
Lionel B
LB
D000818:Animals; D002118:Calcium / Q000037:antagonists & inhibitors* / Q000502:physiology; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D006131:Growth Inhibitors / Q000502:physiology*; D006801:Humans; D016753:Interleukin-10 / Q000502:physiology*; D051379:Mice; D010010:Osteoclasts / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D020239:Receptor Cross-Talk / Q000276:immunology; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology*; D014158:Transcription, Genetic / Q000276:immunology
D006131:Growth Inhibitors; C508609:IL10 protein, human; D053246:Receptor Activator of Nuclear Factor-kappa B; D011971:Receptors, Immunologic; C473367:TREML2 protein, human; D016753:Interleukin-10; D002118:Calcium