Among the arachidonic acid metabolites, PGE2 is by far the most widely tested substance in terms of its capacity to modify OTM. Evidence, mainly derived from animal studies, points toward a positive effect of PGE2 with respect to enhancing bone resorption and accelerating tooth movement (Yamasaki et al., 1982, 1984; Leiker et al., 1995; Kale et al., 2004). The few available clinical studies are of low quality and involve repeated injections of PGE2 and follow-up times of a maximum of 60 days (Camacho and Velásquez Cujar, 2014). The mode of application of PGE2 is a major limitation as it involves repeated injection (due its short half-life) in combination with an anaesthetic solution to alleviate the hyperalgesia caused by injection of PGE2. Potential adverse effects (e.g., root resorption) linked to long-term administration of PGE2, as required in the context of orthodontic treatment, are possible given its mode of action but have not been evaluated so far.

Specific synthases are involved in the pathway of the synthesis of each type of prostaglandins (e.g., PGE and PGD synthases) and many of them have been cloned and could provide drug targets for the regulation of the synthesis of specific prostaglandins, such as PGE2 in the case of OTM (Forsberg et al., 2000). In addition, it is possible that other PGs such as PGI2 may be involved in bone resorption providing further targets for drugs (Wang et al., 1999). Another obvious group of drug targets are the identified receptors of specific prostaglandins (such as the receptors EP1, EP2, or EP4 of prostaglandin PGE2) and the design of selective agonists can provide pharmacological methods of modifying OTM through these receptors.

Intravenous immunoglobulin (IVIg) preparations are polyspecific and polyclonal immunoglobulin therapeutic preparations used as a replacement therapy in immunodeficient patients (Grader-Beck et al., 2011; Schneider et al., 2015). These IVIg preparations were shown to induce COX-2 mediated PGE2 synthesis and cytokine production (Trinath et al., 2013; von Gunten et al., 2013; Djoumerska-Alexieva et al., 2015). It is possible that local administration of these IVIg preparations could be used to modulate bone modeling through PEG2 induction and bypass some of the limitations of PEG2 injections.

Parathyroid hormone (PTH) exerts its effects directly on osteoblasts and indirectly on osteoclasts through binding to the PTH type 1 receptor on osteoblasts, leading to expression of insulin-like growth factor-1 (IGF-1), which promotes osteoblastogenesis and osteoblast survival, and of RANKL, which promotes osteoclast activation. PTH is also likely interacting with bone lining cells promoting early osteogenesis (Dobnig and Turner, 1995; Esbrit and Alcaraz, 2013)

Recombinant PTH is clinically used for the treatment of osteoporosis and has been shown to mediate bone anabolic or catabolic effects depending on the circumstances of administration (Esbrit and Alcaraz, 2013). Intermittent exposure to PTH seems to increase bone formation, while continuous and long-term exposure (longer than 1–2 years) enhances bone resorption. Studies on the effects of PTH on tooth movement point toward a role of intermittent treatment with PTH in facilitating bone remodeling/turnover and therefore accelerating tooth movement. This is possibly occurring by PTH enhancing both osteoblast and subsequently also osteoclast activity (Li et al., 2013). To date there no long-term studies employing local PTH delivery that discriminate between effects of PTH on tooth movement when different protocols are used (short-term vs. long-term administration and intermittent or continuous mode of administration). Some short-term animal studies indicate that a system of slow, continuous release of PTH in areas of compression is able to accelerate OTM (Soma et al., 1999, 2000).

1,25-dihydroxycholecalciferol or calcitriol is the most active metabolite of vitamin D and has predominantly anabolic, but also catabolic effects on bone. Furthermore, vitamin D also modulates the transcription of genes in immune cells (von Gunten et al., 2013). Calcitriol seems to enhance bone remodeling in a similar way to PTH by enhancing osteoblastic proliferation and function (Reichel et al., 1989), while both PTH and 1,25-dihydroxycholecalciferol have been shown to stimulate PG production in osteoblasts further implicating them in the process of OTM (Pilbeam et al., 1989; Klein-Nulend et al., 1991). Some evidence from animal experiments exists on the effect of local application of calcitriol on tooth movement (Takano-Yamamoto et al., 1992; Kale et al., 2004; Kawakami and Takano-Yamamoto, 2004). During the short experimental time of the available studies there is some evidence that calcitriol enhances the processes of alveolar bone resorption and formation (bone remodeling) leading to acceleration of tooth movement during force application (Takano-Yamamoto et al., 1992; Kale et al., 2004), and also enhances bone formation and remodeling after OTM (Kawakami and Takano-Yamamoto, 2004). A clinical study testing the effects of systemic application of calcitriol indicated that it may produce some enhancement in tooth movement (Blanco et al., 2001).

Relaxin is a peptide hormone with strong effects on collagen turn-over. In vitro studies have suggested that relaxin may have a direct effect on the PDL by means of decreasing the expression and release of collagen type I, increasing expression of certain MMPs and decreasing the expression of inhibitors of metalloproteinases (TIMPs), (Henneman et al., 2008; Takano et al., 2008, 2009) in PDL cells. Despite increased interest in the potential of relaxin to modulate OTM, effects on tooth movement and tooth stabilization could to date not be confirmed, neither clinically (McGorray et al., 2012) nor in animal experiments (Stewart et al., 2005; Madan et al., 2007).

The potential use of osteoprotegerin (OPG) to inhibit tooth movement and enhance stability, stems from the known physiological role that OPG plays within the PDL in regulating the bone resorbing activity of osteoclasts. OPG is produced by osteoblasts and is a decoy receptor for RANKL which prevents the interaction of RANKL present on osteoblasts' surface with its receptor RANK on osteoclasts. In the absence of RANKL-RANK interactions, the activation, terminal differentiation and survival of osteoclasts are negatively affected. Changes in the ratio of RANKL/OPG in the PDL can fine-tune alveolar bone resorption. A number of groups attempted to influence tooth movement in animal models by locally altering the concentration of either OPG or RANKL aiming to enhance or decrease the resorptive action of osteoclasts (Kanzaki et al., 2004, 2006; Dunn et al., 2007; Zhao et al., 2012). A local gene transfer method to increase the expression of either OPG or RANKL in periodontal tissues was used in some studies, in which acceleration of tooth movement by gene transfer of RANKL and inhibition by gene transfer of OPG were observed. For the short experimental time periods used, gene transfer is reported to have caused no alterations in bone metabolism in bones distant from the site of injection (Zhao et al., 2012).

Of note is that Denosumab, a humanized monoclonal antibody against RANKL, has recently been added to the list of pharmacological agents used to combat osteoporosis but has not been evaluated with respect to OTM (Bekker et al., 2004; Boyce and Xing, 2008).

Bisphosphonates exert a strong inhibitory effect on bone resorption and are successfully used for the treatment of osteoporosis. With respect to the possible effects of different bisphosphonates on tooth movement, in vitro studies have shown that both aledronate (Kim et al., 2012) and clodronate (Liu et al., 2006) inhibit the stress-induced up-regulation of key components crucial for mediating tooth movement. Clodronate was shown to reproducibly inhibit the stress-induced expression of COX-2, PGE2, and RANKL in cultured human PDL-derived cells in a concentration-dependent manner (Liu et al., 2006). This action of clodronate is likely to indirectly prevent osteoclast formation and allow osteoclast apoptosis. Kim et al. used chitosan scaffolds loaded with aledronate to investigate possible effects of this bisphosphonate on osteoblasts and on RANKL-induced differentiation of osteoclasts (Kim et al., 2012). They observed concentration-dependent positive effects of aledronate on the proliferation, differentiation and activity of osteoblasts, and a potent inhibitory effect on osteoclast differentiation. An interesting aspect of this study was that chitosan aledronate releasing scaffolds seem to ensure a sustained release of aledronate for a period of 4 weeks, suggesting that this system might provide a feasible delivery vehicle for long-term treatment.

Cytokines are released following mechanical stimulation of cells in the PDL. Their effects on initiating tooth movement are mediated through binding to cytokine receptors on target cells. Decreasing the amount of the unbound cytokines could be a possible strategy of reducing tooth movement. This approach was taken in two studies examining the effects of systemic application of soluble cytokine receptors on tooth movement and root resorption in rodents (Zhang et al., 2003; Jäger et al., 2005). The authors concluded that the administration of soluble receptors to IL-1 and TNF-a, or their combination, led to reduction in OTM in all receptor-treated groups by approximately 50% (Jäger et al., 2005). Furthermore, the number and activity of osteoclasts and odontoclasts were reduced.

Another potential approach is to increase the production of osteoclast inhibitory cytokines such as IL-10 and TGF-β. A potential compound with its origins in the chinese medicine is triptolide, which upregulates the production of these cytokines by regulatory T cells (Xu et al., 2016). A water soluble compound of triptolide, minnelide, has recently become available and is currently used in clinical trials to combat pancreatic cancer.

A potential pharmacological approach to decrease bone resorption and tooth movement is through the use of specific chemokine receptor antagonists, such as Met-RANTES, a modified methionylated CCL5 molecule, which binds to both CCR1 and CCR5 receptors and blocks the physiological signaling pathway that leads to bone resorption (Proudfoot et al., 1996; Taddei et al., 2012). Such an intervention could be used to enhance anchorage by preventing the movement of teeth under mechanical loading.

Chemically modified tetracyclines (CMTs) are derivatives of the tetracycline groups of antibiotics that lack antimicrobial activity and the adverse effects associated with the conventional tetracyclines. Their ability to inhibit MMPs and pro-inflammatory cytokines and their apoptotic effects on osteoclasts initially rendered them attractive therapeutic agents for the management of chronic periodontitis. The CMTs have been shown to modify the COX-2 enzyme leading to inhibition of PGE2 production (Patel et al., 1999) and represent also potent inhibitors of MMPs (Marcial et al., 2012). These properties make CMTs a potentially useful pharmacological agent to inhibit tooth movement in order to control anchorage or enhance tooth stability after orthodontic treatment. Initial animal studies (Bildt et al., 2007) showed that oral administration of CMT-3 (now known as COL-3) reduced the rate of tooth movement in rats in a concentration-dependent manner. The exact mechanism of action remains to be elucidated.

Another antibacterial agent, enoxacin, offers an attractive approach for controlling the resorptive activity of osteoclasts. For the resorption of bone mineral, the presence of proton pumps in the ruffled borders of osteoclasts is crucial. To this end, osteoclasts have the unique ability to produce increasing amounts of vacuolar (V) ATPases (proton pumps) upon their activation. These V-ATPases are transported through interaction with microfilaments within the cytoplasm to the plasma membrane- a unique ability limited to clast cells, thus making the targeting of this process a highly specific means for modulation of tooth movement. Enoxacin was first identified by crystal structure-based virtual screening as one of the potential molecules which could block the binding site of V-ATPase to actin (Ostrov et al., 2009). Such interference would in principle prevent transportation of the proton pumps to the ruffled border of the osteoclast. In vitro studies confirmed the predicted effect (Ostrov et al., 2009) and animal studies showed that a modified version of enoxasin (bis-enoxacin) with enhanced binding to bone selectively inhibited osteoclasts resulting in inhibition of tooth movement in rats after 28 days (Toro et al., 2013).

There is also some evidence from in vitro experiments that the well-known antiseptic Cetyl Pyridinium Chloride (CPC) inhibits RANKL-induced osteoclast formation from bone marrow-derived macrophages possibly by supressing a key event in the RANKL induced intracellular signaling pathway or by interfering with M-CFS signaling (Zheng et al., 2013). To our knowledge potential inhibitory effects of CPC on OTM have not been tested to date. Its already approved use in dental medicine due to its antiseptic properties renders CPC an attractive agent to test for potential beneficial effects on tooth stability after orthodontic treatment.

The theoretical possibility that antioxidants may interfere with tooth movement derives from observations that the cellular concentration of reactive oxygen species (ROS) increases under conditions of hypoxia and mechanical stress in PDL fibroblasts and that hypoxia has been shown to lead to the expression of key genes involved in the recruitment and activation of osteoclasts (Janssen-Heininger et al., 2000; Dandajena et al., 2012). Altered ROS levels also influence the characteristics of immune cells (Wehrli et al., 2014).

The effects of antioxidants (either resveratrol or N-acetylcysteine) were tested in a split mouth design in rats (Chae et al., 2011). The authors reported a significant decrease in tooth movement compared to the control sites following local injection of N-acetylcysteine but not resveratrol.

Integrins are a group of transmembrane glycoproteins, which form heterodimeric units on the membrane of PDL clast cells, such as osteoclasts and odontoclasts (Talic et al., 2004). One of their functions is the adhesion of the differentiated clast cells onto specific proteins on bone (e.g., osteopontin) and dentine enabling them to become polarized and start the bone resorption process, but members of the group mediate other functions such as clast cell migration, cell differentiation and survival.

Integrin molecules adhere to proteins containing RGD (standing for the amino acids arginine, glycine and aspartate) epitopes. Such proteins include osteopontin and bone sialoprotein (Miyauchi et al., 1991). This property has been exploited and a number of studies have used RGD-containing peptides as antagonists to prevent integrin function. With respect to tooth movement, based on results from animal models it appears that there is the potential for RGD peptides to inhibit tooth movement (Dolce et al., 2003) and also root resorption (Talic et al., 2006). There is, however, indication from the experimental results that a more detailed knowledge of the function of the different integrin molecules is crucial, as generalized inhibition of integrin function at PDL sites may have a multitude of undesirable effects.

Another potential means of exploring the role of RGD peptides and inhibiting tooth movement is through the use of MMP inhibitor molecules to reduce the production of RGD peptides by MMPs in areas of compression (Holliday et al., 2003). This animal study used a general (rather than specific) MMP inhibitor, Ilomastat, locally delivered and demonstrated some reduction in bone resorptive osteoclast activity.