Biological Mechanisms of Tooth Movement. Группа авторов
PG synthesis (Leclerc et al., 2013), suggesting that an inducer‐first messenger (PG) cascade can take place in the development of an inflammatory reaction to orthodontic forces. Also, DAMP‐induced PG can modulate cytokines, demonstrating the existence of complex regulatory networks involving different classes of mediators in the response to orthodontic forces (Prockop and Oh, 2012). Therefore, it may be concluded that PGs play an important role in OTM.
The second‐messenger system
According to Krishnan and Davidovitch (2006a), while paradental tissues become progressively strained by applied forces, their cells are continuously subjected to other first messengers, derived from cells of the immune and nervous systems. The binding of these signal molecules to cell membrane receptors leads to enzymatic conversion of cytoplasmic ATP and GTP into adenosine 3´,5´‐monophosphate (cyclic AMP [cAMP]), and guanosine 3´,5´‐monophosphate (cyclic GMP [cGMP]), respectively. These latter molecules are known as intracellular second messengers. Immunohistochemical staining during OTM in cats showed high concentrations of these molecules in the strained paradental tissues (Davidovitch et al., 1988).
Internal cellular signaling systems are those that translate many external stimuli into a narrow range of internal signals or second messengers (Sandy et al., 1993). Cyclic AMP and cGMP are two second messengers associated with bone remodeling. Bone cells, in response to hormonal and mechanical stimuli, produce cAMP in vivo and in vitro. Alterations in cAMP levels have been associated with synthesis of polyamines, nucleic acids, and proteins, and with secretion of cellular products. The action of cAMP is mediated through phosphorylation of specific substrate proteins by its dependent protein kinases. In contrast to this role, cGMP is considered an intracellular regulator of both endocrine and nonendocrine mechanisms (Davidovitch, 1995). The action of cGMP is mediated through specific substrate proteins by cGMP‐dependent protein kinases. This signaling molecule plays a key role in the synthesis of nucleic acids and proteins, as well as secretion of cellular products.
According to Meikle (2006), the second messenger system classically associated with mechanical force transduction is cAMP. The first evidence for the involvement of the cAMP pathway in mechanical signal transduction was provided independently by Rodan et al. (1975), and by Davidovitch and Shanfeld (1975). Rodan et al. (1975) showed that a compressive force of 60 g/cm2 applied to 16‐day‐old chick tibia in vitro inhibited the accumulation of cAMP in the epiphyses, as well as in cells isolated from the proliferative zone of the growth plate. The effect was mediated by an enhanced uptake of Ca2+ which inhibited membrane‐associated adenyl cyclase activity.
Davidovitch and Shanfeld (1975) sampled alveolar bone from compression and tension sites surrounding orthodontically tipped canines in cats. They found that cAMP levels initially decreased, followed by an increase after 1–2 days, which remained elevated to the end of the experimental period of 28 days. They suggested that the initial decrease at the compression sites was due to necrosis of PDL cells, and at the tension sites to a rapid increase in the cell population; the elevation in cAMP observed 2 weeks after the initiation of treatment was probably a reflection of increased bone remodeling activity. Subsequently, Davidovitch et al. (1976), in a study on the cellular localization of cAMP in the same model, found an increase in the number of cAMP‐positive cells in areas of the PDL where bone resorption or deposition subsequently occurred. Osteocytes in the adjacent alveolar bone, however, appeared to be relatively unaffected by the mechanical force.
Cytokines
Cytokines are proteins that act as signals between the cells of the immune system. These molecules are produced during the activation of immune cells and usually act locally, although some act systemically with overlapping functions. Depending on the major outcomes driven by different cytokines, they can be didactically grouped into subfamilies such as interleukins (the broader group comprising pleiotropic cytokines initially nominated as the mediators of the communication “between leukocytes”), TNF superfamily (comprising TNF‐α and the RANK/RANKL/OPG [receptor activator of nuclear factor kappa B ligand/osteoprotegerin] system, the major regulators of the osteoclastogenesis process), chemokines (cytokines with primary chemotactic function), and growth factors (cytokines having prominent actions in proliferative and differentiation processes).
Previous studies have implicated the involvement of different classes of cytokines in bone remodeling in vitro and in vivo. These cytokines are considered as key mediators involved in a variety of immune and acute‐phase inflammatory response activities. The role of the immune system in the regulation of bone remodeling through cytokine production by inflammatory cells that have migrated from dilated PDL capillaries after the application of orthodontic forces is well established (Davidovitch et al., 1988).
Interleukins
IL‐1 exists in two forms, α and β, of which IL‐1β is the form mainly involved in bone metabolism, stimulation of bone resorption, and inhibition of bone formation. IL‐1β also plays a central role in the inflammatory process. The staining of feline PDL cells for IL‐1β showed the presence of bound signal complexes in the plasma membrane, which was expected as it is known that receptors for IL‐1β are present on fibroblasts (Dinarello and Savage, 1989). The response of gingival fibroblasts to IL‐1 might represent a mechanism for amplification of gingival inflammation. Further, IL‐1β may act synergistically with TNF‐α as a powerful inducer of IL‐6. Recent studies have described positive correlations between IL‐1β gingival crevicular fluid (GCF) levels and the rate of OTM, derived from low‐level laser therapy application (Varella et al., 2018; Fernandes et al., 2019).
IL‐6, a multifunctional cytokine previously referred to as B cell stimulatory factor 2, hepatocyte stimulating factor, or interferon‐α2, is produced by both lymphoid and nonlymphoid cells. This cytokine can apparently induce osteoclastic bone resorption through an effect on osteoclastogenesis. The levels of IL‐1β and IL‐6 were significantly higher in inflamed gingivae, when compared with non‐inflamed gingival tissues in young adults. The finding that there is an elevation in levels of IL‐1α and β, and IL‐6 in the PDL and alveolar bone (Figure 4.2) following mechanical force application was demonstrated through in vivo studies (Davidovitch et al., 1988; Alhashimi et al., 2001; Bletsa et al., 2006) and in 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