types of mediators can fit in the growth factor description, including a series of cytokines, TGF‐β being the prototypic example.
TGF‐β is a pleiotropic cytokine that can regulate cell growth, differentiation, and matrix production. Generally, TGF‐β has an anabolic nature, increasing the proliferation and chemotaxis of PDL cells, and upregulating the expression of COL‐I (Matsuda et al., 1992; Sporn and Roberts, 1993; Chang et al., 2002). TGF‐β also presents anabolic properties on bone tissue, recruiting osteoblast precursors and inducing their differentiation, and enhancing the production of bone matrix proteins (Kanaan and Kanaan, 2006). TGF‐β expression was found to be increased during OTM, being observed in osteoblasts in the tension zone, and in bone‐resorbing osteoclasts in the compression zone (Kobayashi et al., 2000; Dudic et al., 2006), which suggests a broad role for this cytokine in the tooth movement process (Garlet et al., 2007). Barbieri et al. (2013) reported a significant increase in TGF‐β in GCF during OTM at the pressure side. A recent study investigated the potential application of platelet‐rich plasma, characteristically rich in growth factors such as TGF‐β, in experimental OTM in rats. However, no significant effects were observed (Akbulut et al., 2019), suggesting that the endogenous levels of molecules may be sufficient to promote an effective tooth movement.
Matrix metalloproteinases (MMPs)
These agents are zinc‐ion‐dependent proteolytic enzymes, produced by a wide variety of cells during developmental processes, inflammatory diseases, degenerative articular diseases, tumor invasion, and wound healing. These enzymes are classified into several subgroups, i.e., collagenases (MMP‐1, 8, and 13), gelatinases (MMP‐2 and 9), stromelysins, membrane‐type MMPs, and other subfamilies. Most of the MMPs are produced as pro‐enzymes, cleaved at the specific site to become a mature form, and then secreted and activated in the presence of zinc and calcium ions. The activation of MMPs is also regulated by a group of endogenous proteins named tissue inhibitors of metalloproteinases (TIMPs), which are each capable of inhibiting almost every member of the MMP family in a nonspecific way. The MMPs/TIMPs ratio is supposed to determine the turnover rate of periodontal tissues, and consequently to influence the outcome of OTM (Garlet et al., 2007).
In vivo studies demonstrated that MMP‐1, 2, 3, 8, 9, and 13 were expressed in the PDL and alveolar bone during OTM (Takahashi et al., 2003, 2006; Garlet et al., 2007; Leonardi et al., 2007). Further, in vitro studies also demonstrated that the expression of MMP‐1 and MMP‐2 mRNA in human PDL cells was detected after exposure to mechanical stress (He et al., 2004; Redlich et al., 2004). When MMPs and TIMPs were investigated simultaneously in PDL under orthodontic forces, higher MMP‐1 levels were found in the compression than in the tension side, while TIMP‐1 levels were upregulated in the tension area (Garlet et al., 2007), suggesting that there exists a differential pattern of expression providing distinct microenvironments favorable for extracellular matrix synthesis or degradation. The role of the MMP system in the regulation of OTM was experimentally confirmed, since the inhibition of MMPs activity with chemically modified tetracyclines, or by anti‐inflammatory or immunosuppressive drugs (such as potassium diclofenac and dexamethasone), inhibited experimental tooth movement in rats (Bildt et al., 2007; Molina Da Silva et al., 2017).
Neuropeptides
According to Lundy and Linden (2004) it is generally accepted that the nervous system contributes to the pathophysiology of peripheral inflammation, and a neurogenic component has been implicated in many inflammatory diseases including periodontitis. Neurogenic inflammation should be regarded as a protective mechanism, which forms the first line of defense and protects tissue integrity. Sensory neuropeptides play important roles in neurogenic inflammation, including vasodilatation, plasma extravasation, and recruitment of immune cells. However, a more extensive function for neuropeptides in the regulation of immune cell activity has also been proposed. During inflammation, there is a sprouting of peptidergic peripheral fibers and increased neuropeptide content.
Substance P and neurokinin A
SP and neurokinin A (NKA) are members of the tachykinin (tachy‐swift) neuropeptide family, and as such evoke rapid responses upon release. They exert a wide variety of biological actions and are intimately linked with neurogenic inflammation. The intensity of neurogenic inflammation has been shown to have a dose‐dependent relationship with the levels of SP and/or NKA. SP causes vasodilatation by acting directly on smooth‐muscle cells and indirectly by stimulating histamine release from mast cells in a concentration‐dependent manner. Increased microvascular permeability, edema formation, and subsequent plasma protein extravasation are prominent peripheral effects of the tachykinins, underlying their powerful proinflammatory properties. The SP‐induced contraction of endothelial cells and subsequent plasma extravasation allow substances such as bradykinin and histamine to gain access to the site of injury and to afferent nerve terminals. SP also interacts with other neurotransmitters: indeed, the characteristic edema formation mediated by SP has been shown to be modulated by nitrous oxide (Hughes et al., 1990). Lee et al. (2007), who outlined the mechanism of action of SP on OTM, demonstrated increased expression of the chemokine C–C ligand (CCL) 20 mRNA, CCL20 protein, and heme oxygenase (HO)‐1 in a dose‐ and time‐dependent manner. SP is also responsible for initiating phosphorylation of IkappaB, degradation of IkappaB, and activation of nuclear factor (NF)‐kappaB. This reaction confirms the role of SP, along with other immunoregulators, in inducing HO‐1, and the inflammatory mediator macrophage inflammatory protein (MIP)‐3 alpha/CCL20 in PDL cells in the development of inflammation associated with OTM.
Calcitonin gene‐related peptide
CGRP is widely distributed throughout the central and peripheral nervous systems and is found at particularly high levels in sensory nerves. CGRP has potent vasodilator activity and is frequently co‐localized with SP. Bone tissue contains CGRP‐immunoreactive nerve fibers, whose increased concentrations during bone development and regeneration suggest that they are directly involved in the local regulation of bone remodeling. Further evidence shows that CGRP, which is derived from alternative splicing of calcitonin gene mRNA, plays a role in bone metabolism. It inhibits osteoclastic bone resorption by directly blocking osteoclast activation, or by indirectly regulating the osteoblast release of cytokines such as interleukin‐1 and TNF‐α, which can affect osteoclast function.
Villa et al. (2006) reported that CGRP influences the process of mechanically induced bone remodeling through its pro‐osteoclastogenic effect on the OPG/RANK/RANKL triad. Through this mechanism, it reduces OPG release and expression by hOB (human osteoblast‐like cells). Their results also demonstrated that the cAMP/PKA pathway is involved in the CGRP inhibition of OPG mRNA and protein secretion by hOB, and that this effect favors osteoclastogenesis. CGRP could thus modulate the balance between osteoblast and osteoclast activity, participating in the fine‐tuning of all of the bone remodeling phases necessary for the subsequent anabolic effect.
Vasoactive intestinal polypeptide
VIP is another neuropeptide with immunosuppressive properties. VIP is one of a group of regulatory molecules termed macrophage‐deactivating factors that are believed to prevent the excessive production of proinflammatory cytokines. Since the mid‐1990s, VIP has been identified as an important immunomodulatory peptide, capable of regulating the production of both pro‐ and anti‐inflammatory mediators. Interestingly, VIP can also counteract the inflammatory effects of DAMPs, suggesting that neural–immunological regulatory pathways can operate in the regulation of force‐induced OTM (Chorny and Delgado, 2008).
Neuropeptide Y
Neuropeptide
