G Protein-Coupled Receptor 120 Signaling Negatively Regulates Osteoclast Differentiation, Survival, and Function.
G protein-coupled receptor 120 (GPR120) plays an important role in the regulation of inflammation and lipid metabolism. In this study, we investigated the role of GPR120 in osteoclast development and found that GPR120 regulates osteoclast differentiation, survival and function. We observed that GPR120 was highly expressed in osteoclasts compared to their precursors, bone marrow-derived macrophages (BMMs). Activation of GPR120 by its ligand GW9508 suppressed receptor activator of NF- κB ligand (RANKL)-induced osteoclast differentiation and the expression of nuclear factor of activated T cells c1 (NFATc1), a key modulator of osteoclastogenesis. GPR120 activation further inhibited the RANKL-stimulated phosphorylation of IκBα and JNK. In addition to osteoclast differentiation, GPR120 activation increased the apoptosis of mature osteoclasts by inducing caspase-3 and Bim expression. Activation of GPR120 also interfered with cell spreading and actin cytoskeletal organization mediated by M-CSF but not by RANKL. Coincident with the impaired cytoskeletal organization, GPR120 activation blocked osteoclast bone resorbing activity. Furthermore, knockdown of GPR120 using small hairpin RNA abrogated all these inhibitory effects on osteoclast differentiation, survival, and function. Together, our findings identify GPR120 as a negative modulator of osteoclast development that may be an attractive therapeutic target for bone-destructive diseases. J. Cell. Physiol. 231: 844-851, 2016. © 2015 Wiley Periodicals, Inc.
Department of Molecular Medicine, Cell and Matrix Research Institute, Clinical Trial Center, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Korea.
Hyun-Ju
HJ
Kim
Department of Molecular Medicine, Cell and Matrix Research Institute, Clinical Trial Center, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Korea.
Hye-Jin
HJ
Yoon
Department of Molecular Medicine, Cell and Matrix Research Institute, Clinical Trial Center, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Korea.
Bo Kyung
BK
Kim
Department of Molecular Medicine, Cell and Matrix Research Institute, Clinical Trial Center, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Korea.
Woo Youl
WY
Kang
Department of Molecular Medicine, Cell and Matrix Research Institute, Clinical Trial Center, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Korea.
Sook Jin
SJ
Seong
College of Pharmacy, Yeungnam University, Gyeonsan, Korea.
Mi-Sun
MS
Lim
Department of Orthopedic Surgery, Kyungpook National University School of Medicine, Daegu, Korea.
Shin-Yoon
SY
Kim
Department of Molecular Medicine, Cell and Matrix Research Institute, Clinical Trial Center, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Korea.
Young-Ran
YR
Yoon
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects; D053245:RANK Ligand / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
C498007:FFAR4 protein, mouse; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D053245:RANK Ligand; D043562:Receptors, G-Protein-Coupled