G protein-coupled receptor 119 is involved in RANKL-induced osteoclast differentiation and fusion.
Hyun-Ju KimHye-Jin YoonJi-Wan ParkXiangguo CheXian JinJe-Yong ChoiPublished in: Journal of cellular physiology (2018)
G protein-coupled receptor 119 (GPR119) is known to be a promising therapeutic target for type 2 diabetes. Recently, it has been reported that the GPR119 agonist increases bone mineral density in an animal model of diabetes, suggesting that GPR119 may play a key role in bone metabolism. In this study, we investigated the functional role of GPR119 in receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation. We found that the GPR119 expression was markedly increased in preosteoclasts and then downregulated in mature osteoclasts. Activation of GPR119 with AS1269574, a potent selective agonist for GPR119, inhibited the generation of multinuclear osteoclasts from bone marrow-derived macrophages. Confirming this observation, targeted silencing of GPR119 using short hairpin RNA abrogated the AS1269574-mediated suppressive effect on osteoclast formation. GPR119 activation attenuated the expression of c-Fos and nuclear factor of activated T cells cytoplasmic 1 (NFATc1) and blocked RANKL-stimulated phosphorylation of IκBα, c-Jun N-terminal protein kinase (JNK), and extracellular signal-regulated kinase (ERK) but not p38. In addition, GPR119 activation suppressed preosteoclast fusion by downregulating the expression of the dendritic cell-specific transmembrane (DC-STAMP), a molecule that is essential for cell-cell fusion in osteoclast formation. Furthermore, ectopic expression of DC-STAMP restored AS1269574-mediated inhibition of osteoclast fusion. Taken together, our findings demonstrate that GPR119 plays a negative role in osteoclast differentiation and fusion induced by RANKL, and therefore may represent a potential target for bone resorption-associated diseases.
Keyphrases
- bone loss
- nuclear factor
- fatty acid
- bone mineral density
- toll like receptor
- type diabetes
- poor prognosis
- dendritic cells
- protein kinase
- signaling pathway
- cardiovascular disease
- postmenopausal women
- immune response
- binding protein
- cell proliferation
- transcription factor
- inflammatory response
- cell therapy
- oxidative stress
- insulin resistance
- diabetic rats
- induced apoptosis
- anti inflammatory
- risk assessment
- cell death
- pi k akt
- high resolution
- mesenchymal stem cells
- cancer therapy
- stress induced