Читать книгу Biological Mechanisms of Tooth Movement - Группа авторов - Страница 62

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. The higher force magnitudes did not increase RANKL expression or osteoclasts counts or amount of tooth movement. This suggests that after a certain magnitude of force, there is a saturation in the biological response, which does not support the concept of higher forces application to accelerate the rate of tooth movement (Alikhani et al., 2015).

It is also important to consider that RANKL and OPG expression may be decisively modulated by cytokines. Indeed, it was previously demonstrated that higher TNF‐α expression on the compression side possibly drives the upregulation of RANKL; higher levels of IL‐10 are supposed to increase OPG expression on the tension side (Garlet et al., 2007). Recent studies point to sclerostin as an additional important regulator of RANKL along OTM (Odagaki et al., 2018; Ohori et al., 2019), reinforcing the complexity of the RANK system regulation. It is therefore suggested that the RANKL–RANK system is directly involved in regulation of OTM (Figure 4.3).

Figure 4.3 Immunohistochemical staining for RANKL in PDL after 7 days during tooth movement. Rat PDL specimens were composed of relatively dense connective tissue fibers and fibroblasts that regularly ran in a horizontal direction from the root cementum toward the alveolar bone. Blood capillaries were mainly recognized near the alveolar bone in the PDL. The alveolar bone and root surface were relatively smooth, but only a few mononuclear and multinucleate osteoclasts and resorption lacunae were rarely observed on the alveolar bone surface (A). Some of these mononuclear and multinucleate osteoclasts were positive to TRAP (B). On 1 day after tooth movement, the arrangement of the fibers and fibroblasts become coarse and irregular, and blood capillaries were pressured (C). Resorption lacunae with a few TRAP‐positive multinucleate osteoclasts were observed on the surface of the alveolar bone and root (D). Three days after tooth movement, the PDL was composed of coarse arrangement of fibers and expanded blood capillaries (E). Many resorption lacunae with TRAP‐positive multinucleate osteoclasts appeared on the alveolar bone surface, while in the fibers of the PDL, many mononuclear TRAP‐positive cells were present (F). Seven days after tooth movement, fibroblasts in the PDL were increased (G). Further, on the surface of the alveolar bone, bone resorption lacunae with multinucleate TRAP‐positive osteoclasts were recognized. Mononuclear TRAP‐positive cells were decreased in comparison with these 3 days after the movement (H). The immunoreactivity of RANKL was weakly localized in cytoplasm of some fibroblasts and pericytes near the alveolar bone surface (I). One day after tooth movement, RANKL positive fibroblasts in the PDL and osteoblasts at the bone surface were increased (J). Three days after tooth movement, many RANKL positive osteoclasts and fibroblasts were observed. The immunoreactivity to RANKL of the fibroblasts become more strong (K). Seven days after movement, the immunoreactivity of RANKL was observed in the fibroblasts and osteoclasts on the alveolar bone surface, but the degree was decreased (L).

CD40, another member of the TNF superfamily, is a cell surface receptor seen in a variety of inflammatory and resident cells. Cellular responses mediated by CD40 are triggered by its counter receptor CD40L, which also belongs to the TNF gene family. It was found that CD40–CD40L interaction appears to be an active process during OTM, and that orthodontic force induces T‐cell activation (Hayashi et al., 2012). Such activation might be involved in the induction of inflammatory mediators and subsequent bone remodeling (Alhashimi et al., 2004). Indeed, it has been suggested that OPG exists in both membrane‐bound and soluble forms and that its expression is up‐regulated by CD40 stimulation.