Potential roles for S P in angiogenesis cancer and

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 TBB (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].