--- - |2- G protein‐coupled receptor 119 (GPR119) activation inhibits osteoclastogenesis and fusion induced by receptor activator of nuclear factor‐κB ligand (RANKL). GPR119 may become a new target for the treatment of bone‐erosive diseases characterized by increased osteoclast number. Abstract 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. - 'Journal of Cellular Physiology, EarlyView. '