biochemical agents such as PG has been suggested as one effective method that significantly increases OTM (Yamasaki et al., 1980; Yamasaki, 1983). The mechanism of action of PGE2 can be explained by the pressure–tension theory of tooth movement, which assumes chemical signals to be cell stimulants that lead to tooth movement (Rygh, 1989). According to this theory, pressure causes changes in the PDL blood circulation and the resultant release of chemical mediators. Inflammatory mediators may act in concert and produce synergistic potentiation of prostanoid formation in cells of the human PDL (Ransjo et al., 1998). There is evidence that PG is released when cells are mechanically deformed (Rodan et al., 1975). Indeed, in vitro studies have shown that the expression and production of PGE2 is promoted by mechanical stimulation of the PDL (Yamaguchi et al., 1994). COX‐2 is induced in PDL cells by cyclic mechanical stimulation and is responsible for the augmentation of PGE2 production in vitro (Shimizu et al., 1998). Furthermore, PGE2 plays an important role as a mediator of bone remodeling under mechanical forces (Yamasaki et al., 1982). Saito et al. (1991) reported that there is a local increase in PGs in the PDL and alveolar bone during orthodontic treatment, while other studies have demonstrated an arrest in tooth movement in experimental animals when nonsteroidal anti‐inflammatory drugs were administered (Chumbley and Tuncay, 1986). Indomethacin, a specific inhibitor of prostaglandin synthesis, reduced the rate of OTM (Yamasaki et al., 1980). Further, when PGE1 was administered locally or systemically to rats as an adjunct to orthodontic force, accelerated bone resorption and tooth movement were observed (Yamasaki et al., 1984).
Interestingly, HMGB1 can trigger 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
