Proinflammatory cytokine production, cell chemotaxis, and osteoclastogenesis can 
lead to inflammatory bone loss. Previously, we showed that 
sphingosine-1-phosphate receptor 2 (S1PR2), a G protein coupled receptor, 
regulates inflammatory cytokine production and osteoclastogenesis. However, the 
signaling pathways regulated by S1PR2 in modulating inflammatory bone loss have 
not been elucidated. Herein, we demonstrated that inhibition of S1PR2 by a 
specific S1PR2 antagonist (JTE013) suppressed phosphoinositide 3-kinase (PI3K), 
mitogen-activated protein kinases (MAPKs), and nuclear factor kappa-B (NF-κB) 
induced by an oral bacterial pathogen, Aggregatibacter actinomycetemcomitans, 
and inhibited the release of IL-1β, IL-6, TNF-α, and S1P in murine bone marrow 
cells. In addition, shRNA knockdown of S1PR2 or treatment by JTE013 suppressed 
cell chemotaxis induced by bacteria-stimulated cell culture media. Furthermore, 
JTE013 suppressed osteoclastogenesis and bone resorption induced by RANKL in 
murine bone marrow cultures. ShRNA knockdown of S1PR2 or inhibition of S1PR2 by 
JTE013 suppressed podosome components, including PI3K, Src, Pyk2, integrin β3, 
filamentous actin (F-actin), and paxillin levels induced by RANKL in murine bone 
marrow cells. We conclude that S1PR2 plays an essential role in modulating 
proinflammatory cytokine production, cell chemotaxis, osteoclastogenesis, and 
bone resorption. Inhibition of S1PR2 signaling could be a novel therapeutic 
strategy for bone loss associated with skeletal diseases.