Abstract
As G protein coupled receptors, sphingosine-1-phosphate receptors (S1PRs) have recently gained attention for their role in modulating inflammatory bone loss diseases. Notably, in murine studies inhibiting S1PR2 by its specific inhibitor, JTE013, alleviated osteoporosis induced by RANKL and attenuated periodontal alveolar bone loss induced by oral bacterial inflammation. Treatment with a multiple S1PRs modulator, FTY720, also suppressed ovariectomy-induced osteoporosis, collagen or adjuvant-induced arthritis, and apical periodontitis in mice. However, most previous studies and reviews have focused mainly on how S1PRs manipulate S1P signaling pathways, subsequently affecting various diseases. In this review, we summarize the underlying mechanisms associated with JTE013 and FTY720 in modulating inflammatory cytokine release, cell chemotaxis, and osteoclastogenesis, subsequently influencing inflammatory bone loss diseases. Studies from our group and from other labs indicate that S1PRs not only control S1P signaling, they also regulate signaling pathways induced by other stimuli, including bacteria, lipopolysaccharide (LPS), bile acid, receptor activator of nuclear factor κB ligand (RANKL), IL-6, and vitamin D. JTE013 and FTY720 alleviate inflammatory bone loss by decreasing the production of inflammatory cytokines and chemokines, reducing chemotaxis of inflammatory cells from blood circulation to bone and soft tissues, and suppressing RANKL-induced osteoclast formation.
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]
Our studies revealed that S1PR2 controls cell adhesion units induced by RANKL in bone marrow derived monocytes and macrophages (BMMs), which influence both osteoclastogenesis and bone resorption
RANKL stimulated the up-regulation of podosome components, which were suppressed by treatment with either S1PR2 shRNA or JTE013 compared with controls [43]
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]. Inflammatory cytokines and chemokines recruit monocytes from blood circulation to bone and surrounding soft tissues Following such recruitment, the monocytes undergo differentiation, adhesion, and fusion to form giant multinucleated osteoclasts. Other inflammatory cytokines, such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α, are implicated in osteoclast formation in periodontal diseases, postmenopausal osteoporosis, and rheumatoid arthritis [7,8,9] These inflammatory cytokines fail to induce osteoclastogenesis in monocyte culture in the absence of RANKL, suggesting indirect mechanisms of action. Studies have revealed that these inflammatory cytokines function by promoting RANKL production, reducing OPG production, and/or up-regulating RANK on osteoclast precursors, indirectly affecting osteoclastogenesis [4,10,11] These inflammatory cytokines inhibit osteoblast proliferation [12,13] and disrupt unidirectional osteoblast alignment [14,15], resulting in improper bone regeneration. This sharp gradient between the S1P level in the tissues and the S1P level in the blood controls the migration of immune cells from blood to peripheral tissues, subsequently influencing inflammatory responses in the tissues [16,27,28]
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