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G protein‐coupled receptor 84 controls osteoclastogenesis through inhibition of NF‐κB and MAPK signaling pathways
Author(s) -
Park JiWan,
Yoon HyeJin,
Kang Woo Youl,
Cho Seungil,
Seong Sook Jin,
Lee Hae Won,
Yoon YoungRan,
Kim HyunJu
Publication year - 2018
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.26035
Subject(s) - rankl , osteoclast , chemistry , gene knockdown , microbiology and biotechnology , mapk/erk pathway , rank ligand , nf κb , receptor , activator (genetics) , transcription factor , signal transduction , biology , biochemistry , apoptosis , gene
GPR84, a member of the G protein‐coupled receptor family, is found predominantly in immune cells, such as macrophages, and functions as a pivotal modulator of inflammatory responses. In this study, we investigated the role of GPR84 in receptor activator of nuclear factor‐κB ligand (RANKL)‐induced osteoclast differentiation. Our microarray data showed that GPR84 was significantly downregulated in osteoclasts compared to in their precursors, macrophages. The overexpression of GPR84 in bone marrow‐derived macrophages suppressed the formation of multinucleated osteoclasts without affecting precursor proliferation. In addition, GPR84 overexpression attenuated the induction of c‐Fos and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), which are transcription factors that are critical for osteoclastogenesis. Furthermore, knockdown of GPR84 using a small hairpin RNA promoted RANKL‐mediated osteoclast differentiation and gene expression of osteoclastogenic markers. Mechanistically, GPR84 overexpression blocked RANKL‐stimulated phosphorylation of IκBα and three MAPKs, JNK, ERK, and p38. GPR84 also suppressed NF‐κB transcriptional activity mediated by RANKL. Conversely, GPR84 knockdown enhanced RANKL‐induced activation of IκBα and the three MAPKs. Collectively, our results revealed that GPR84 functions as a negative regulator of osteoclastogenesis, suggesting that it may be a potential therapeutic target for osteoclast‐mediated bone‐destructive diseases.