Abstract
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.
Highlights
Local or systemic bone loss occurs in many human diseases, including rheumatoid arthritis, systemic lupus erythematosus, axial spondyloarthritis, psoriatic arthritis, inflammatory bowel disease, postmenopausal osteoporosis, and periodontitis [1]
We showed that bone marrow-derived monocytes and macrophages (BMMs) derived from SK1 deficient mice reduced S1P generation induced by an oral bacterial pathogen, Aggregatibacter actinomycetemcomitans (Aa), and that SK1 deficiency in mice alleviated periodontal alveolar bone loss induced by Aa [8]
We demonstrated that sphingosine-1-phosphate receptor 2 (S1PR2) regulated the phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinases (MAPKs), and NF-κB signaling cascades induced by the oral bacterial pathogen, as well as modulated the expressions of the podosome protein kinases (PI3K, Src, and Pyk2) and the adhesive proteins (F-actin, integrins, and paxillin) induced by receptor activation of nuclear factor kappa-B ligand (RANKL), subsequently affecting osteoclastogenesis and bone resorption
Summary
Local or systemic bone loss occurs in many human diseases, including rheumatoid arthritis, systemic lupus erythematosus, axial spondyloarthritis, psoriatic arthritis, inflammatory bowel disease, postmenopausal osteoporosis, and periodontitis [1]. These diseases are characterized by high levels of proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and receptor activation of nuclear factor kappa-B ligand (RANKL) [1,2,3,4,5]. Inflammatory conditions are associated with high levels of a bioactive sphingolipid, sphingosine-1-phosphate (S1P) [6,7,8].
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