vitro studies (Saito et al., 1991; Shimizu et al., 1994; Yamamoto et al., 2006). In a general context, IL‐1β and IL‐6 are associated with inflammatory reaction development and the subsequent osteoclastogenesis, and possibly operate in a cooperative way in order to promote tooth movement. Accordingly, the IL‐1Ra, a naturally occurring IL‐1 antagonist, was demonstrated to downregulate OTM in mice (Salla et al., 2012). As described for IL‐1, recent studies have shown positive correlations between IL‐6 GCF levels and the rate of OTM associated with photobiomodulation (Fernandes et al., 2019).
IL‐17 is an inflammatory cytokine that is produced exclusively by activated T cells (Th17 cells) (Yao et al., 1995). IL‐17 has been shown to be an important mediator of autoimmune diseases, including rheumatoid arthritis (Kotake et al., 1999), multiple sclerosis (Ishizu et al., 2005; Lock et al., 2002), and allergic airway inflammation (Molet et al., 2001). Recently, IL‐17 has been reported to induce osteoclastogenesis directly from monocytes alone (Yago et al., 2009). In addition, IL‐17 induces RANKL production by osteoblasts, and was shown to be related to bone destruction in periodontitis (Kotake et al., 1999; Johnson et al., 2004). Moreover, it has been shown that compressive force stimulates the expression of the IL‐17 genes and their receptors in MC3T3‐E1 cells, and also results in the induction of osteoclastogenesis (Zhang et al., 2010). Further, the immunoreactivity for Th17, IL‐17, IL‐17R, and IL‐6 was detected in PDL tissues subjected to orthodontic force on day 7 (Hayashi et al., 2012). Yamada et al. (2013) reported that the immunoreactivities for TRAP, IL‐17, IL‐6, and RANKL in the atopic dermatitis group were found to be significantly increased. The secretion of IL‐17, IL‐6, and RANKL, and the mRNA levels of IL‐6 and RANKL in the atopic dermatitis patients were increased compared with those in healthy individuals when subjected to orthodontic force application. These cytokines may therefore also contribute to alveolar bone remodeling during OTM.
Figure 4.2 Immunohistochemical localization of the cytokine IL‐1α in a 6 μm sagittal section of a maxillary canine from a 1‐year‐old male cat. (a) This section was obtained from a maxillary canine that had not been subjected to orthodontic force (control). A few PDL fibroblasts are stained lightly (brown) for IL‐1α. Light staining intensity is suggestive of a low cellular concentration of the cytokine. (b) This tooth was subjected to 80 g of translatory force for 6 hours. The cells in this photograph are located in the tension zone, and are stained intensely for the cytokine, indicative of high cellular concentrations, compared with the control. Many of the cells appear elongated due to stretching. The round‐shaped cells may have already detached themselves from the stretched extracellular matrix. (c) The cells in the photographs belong to the compression zone. They are stained intensely for IL‐1α. The shape of most cells is round, either because of a reduction in available space due to pressure, or because of cell detachment from the surrounding matrix.
(Source: Courtesy Dr. Ze’ev Davidovitch.)
While some cytokines have been positively associated with the inflammatory reaction and bone resorption occurring during OTMs, others have been described as presenting an inverse effect. The expression of anti‐inflammatory cytokine, IL‐10, is significantly higher on the tension side than the compression side (Garlet et al., 2007). Accordingly, it was demonstrated that tensile strain induces IL‐10 synthesis in PDL (Long et al., 2001). In this context, IL‐10 is supposed to counteract the effect of inflammatory cytokines during the tooth‐movement process and contribute to bone formation in PDL tension areas. Indeed, previous studies demonstrate an important role for IL‐10 in bone metabolism in vivo, as IL‐10‐deficient mice present an increased inflammatory responsiveness, decreased osteoblast generation and bone formation (Claudino et al., 2010). These findings suggest that both pro‐ and anti‐inflammatory interleukins play an important role in mechanical‐force‐induced OTM.
TNF and the RANK/RANKL/OPG system
TNF‐α is a proinflammatory cytokine that is often overexpressed in a number of disease states such as sepsis syndrome, rheumatoid arthritis, inflammatory bowel disease, and periodontitis. The human polymorphonuclear leukocytes derived from alveolar bone can spontaneously produce IL‐1α, IL‐1β and TNF‐α in the site of inflammation, and likely initiate inflammation and regulate augmentation of bone resorption in vivo. In vivo studies demonstrated that TNF‐α was expressed in the PDL and alveolar bone during OTM (Bletsa et al., 2006; Garlet et al., 2007). Indeed, TNF‐α present a central role in tooth movement process, since TNF receptor type 1 deficient mice present a significant decrease in tooth movement in response to orthodontic force (Andrade et al., 2007).
Other cytokines of the TNF‐α family, namely the cytokines of the RANKL/RANK/OPG system, play a critical role in inducing bone remodeling. The TNF‐related ligand RANKL and its two receptors RANK and OPG, have been shown to be involved in this remodeling process (Alhashimi et al., 2001). RANKL is a downstream regulator of osteoclast formation and activation, through which many hormones and cytokines produce their osteoresorptive effect. In the bone system, RANKL is expressed on the osteoblast cell lineage and it exerts its effect by binding to the RANK receptor on osteoclast lineage cells. This binding leads to rapid differentiation of hematopoietic osteoclast precursors to mature osteoclasts. OPG is a decoy receptor produced by osteoblastic cells, which compete with RANK for RANKL binding. The biological effects of OPG on bone cells include inhibition of terminal stages of osteoclast differentiation, suppression of activation of matrix osteoclasts, and induction of apoptosis. Thus, bone remodeling is controlled by a balance between RANK–RANKL binding and OPG production (Theoleyre et al., 2004).
Kanzaki et al. (2002) demonstrated that compressive forces up‐regulated RANKL expression and induction of COX‐2 in human PDL cells in vitro. Aihara et al. (2005) also showed the presence of RANKL in periodontal tissues during experimental tooth movement of rat molars. The number and distribution patterns of RANKL and RANK‐expressing osteoclasts change when excessive orthodontic force is applied to periodontal tissues. Interestingly, different patterns of RANKL/OPG expression are present in PDL tension and compression sites of teeth submitted to orthodontic forces, being the differential balance that is supposed to determine the tissue response outcome (Menezes et al., 2008). Accordingly, compression force significantly increased RANKL and decreased OPG secretion in human PDL cells in a time‐ and force‐magnitude‐dependent manner (Nishijima et al., 2006; Yamaguchi et al., 2006). Accordingly, Kanzaki et al. (2004, 2006) demonstrated that transfer of the RANKL gene to the periodontal tissue activated osteoclastogenesis and accelerated the amount of experimental tooth movement in rats. In contrast, OPG gene transfer inhibited RANKL‐mediated osteoclastogenesis, and inhibited experimental tooth movement. While the exact source(s) of RANKL in PDL area remains to be determined, it was recently demonstrated that deletion in PDL and bone lining cells blocks OTM (Yang et al., 2018). Additionally, mice specifically lacking RANKL in osteocytes present a reduction of OTM (Shoji‐Matsunaga et al., 2017), suggesting that multiple cellular sources may account for the RANKL production in response to orthodontic forces. Interestingly, a recent study demonstrates that an injectable Poly (lactic acid‐co‐glycolic acid: PLGA) formulation containing RANKL, which is able to sustain RANKL for more than 30 days, accelerates OTM in rats (Chang et al., 2019), suggesting a potential translational application.
