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    • 67 7 Potential roles for S P

    2022-07-11

    Potential roles for S1P in angiogenesis, cancer, and autoimmune diseases such as RA have been reported [73]. In RA synoviocytes, S1P has been shown to enhance expression of prostaglandin E2 (PGE2) and cyclooxygenase-2 (COX-2) in response to the pro-inflammatory cytokines, TNF-α and interleukin (IL)-1β [18]. These cytokines production induce expression of matrix metalloproteinases (MMPs) and activate osteoclasts, thereby resulting in bone resorption and soft tissue damage [75]. Osteoclasts themselves also express S1P, and this molecule stimulates the migration of both osteoblasts and mesenchymal stem 67 7 (MSCs). Accordingly, S1P that derives from osteoclasts may attract osteoblasts to areas of bone resorption as one of the first steps in the process of replacing bone that is lost in a damaged area [76]. S1P signaling via S1P1 regulates T cell development and enhances synoviocyte proliferation, inflammatory cytokine expression, and osteoclastogenesis in bone homeostasis [23], [77], [78], [79]. Meanwhile, expression of Sphk1 has been shown to be higher in osteoclasts that have cathepsin K deleted. These osteoblasts also exhibited a higher RANKL/OPG ratio which corresponded with a greater number of osteoclasts present [80]. Differentiation and maturation of osteoclasts require signaling via Sphk1/S1P/S1P3 as previously demonstrated in assays of Runx2 expression and alkaline phosphatase activity [81]. Transforming growth factor (TGF)-β/Smad3 signaling has also been shown to affect cartilage homeostasis by influencing S1P/S1P receptor signaling and chondrocyte migration. Correspondingly, in mice with Smad3-deficient chondrocytes, only the Sphk1/S1P/S1P3 signaling axis was found to play an important role in degradation of the mandibular condylar [82]. The S1P/S1P1 signaling axis controls the migration of osteoclast precursor cells [21], [22], [23], [83] from bone tissues into blood circulation [21] and it may also induce synovial hyperplasia in RA. RANKL stimulation has been found to decrease expression of S1P1 in an NF-κB-dependent manner (Fig. 2) yet not in a NFATc1-dependent manner [21], [23]. Furthermore, RANKL expression during osteoclastogenesis that is induced by the Sphk1/S1P1 signaling axis is the result of interactions between macrophages and bone marrow derived stromal cells (BMSCs) [84]. However, in our recent study, only expression of Sphk1 and S1P1 in MRL/lpr mice increased in the mandibular condyle, and these increases were accompanied by an increase in Rac1 activity (Fig. 3) [21], [65]. Correspondingly, treatment with a S1P1 agonist led to a significant reduction in inflammation and joint destruction, consistent with the predicted actions of the agonist in retaining osteoclast precursor cells [85]. Taken together, these findings suggest that targeting the S1P/S1P1 signaling axis represents a potential treatment for RA [18]. During the development of RA, expression of S1P and S1P1–5 by osteoclasts [65], osteoblasts [81], chondrocytes [82], and MSCs [76], [86] is considered to be essential for modulating cell migration, cell survival, and cytokine or chemokine production during bone formation (Fig. 1) [65], [87]. Therefore, it will be important for future studies to evaluate the role of the S1P/S1P receptor system among the cell-cell interactions that mediate bone homeostasis in TMJ-RA pathogenesis (Fig. 4).
    Role of the NF-κB in osteoclasts NF-κB is an inducible transcription factor that binds a particular DNA sequence that is present in a large number of target genes, especially genes that contribute to immune responses and pathogen defense. In autoimmune diseases, such as RA, NF-κB has an essential role in the differentiation, survival, activation, and development of osteoclasts [88], [89], [90]. Two important proteins in osteoclastogenesis are RANK and its ligand, RANKL (also referred to as TNFRSF11A and TRANCE, respectively). In addition to activating mature osteoclasts, RANKL can combine with M-CSF to regulate osteoclast differentiation from monocyte/macrophage precursor cells [14], [89], [91]. Numerous studies have demonstrated that differentiation of osteoclast precursor cells requires induction of NF-κB activity by RANKL [88], [92], [93], while activation of macrophages and osteoclasts requires NF-κB signaling as well [88], [94].