potent vasoconstrictor and amplifies the postsynaptic effects of other vasoconstrictors such as noradrenaline. The vasoconstrictor activities of NPY in vivo are mediated principally by the NPY Y1 receptor. In addition, NPY has potent angiogenic properties.
Neuropeptides and OTM: A synthesis
Norevall et al. (1995) observed that the expression of CGRP and SP increases in the PDL in response to buccally directed OTM of the upper first molar in the rat. Further, their continuous observations suggest that VIP and NPY, in contrast to the main sensory neuropeptides, CGRP and SP, are not involved in the tissue processes that occur in the remodeling of PDL and alveolar bone during OTM. In relation to tooth movement, Kvinnsland and Kvinnsland (1990) localized CGRP in the pulp and PDL of rats receiving orthodontic forces to maxillary molars for five days. In unstressed teeth, CGRP immunoreactivity was localized primarily in pulp and PDL nerves surrounding blood vessels. In moving teeth, the number of CGRP‐containing nerves in both pulp and PDL increased, and their staining intensified, particularly in PDL tension sites. In these areas, dark “spots,” which were probably fibroblasts that have bound CGRP released from stressed sensory nerve endings, were observed (Figure 4.4). The experimental tooth movement induces dynamic changes in density and distribution of periodontal as well as pulpal nerve fibers, indicating their involvement in both early stages of PDL remodeling and, later, in its regenerative processes, generally occurring in concert with modulation of blood vessels (Vandevska‐Radunovic et al., 1997). The study by Kato et al. (1996) suggested that the neurofilament protein (NFP)‐, CGRP‐, VIP‐ and NPY‐containing nerve fibers in the PDL play important roles in the modulation of pain, tissue remodeling, and blood flow regulation during tooth movement.
Activation of inflammation, apoptosis, and cell cycles of PDL in OTM
Funakoshi et al. (2013) reported increased numbers of TUNEL‐ and caspase 8‐positive PDL cells at day 5 after the application of an orthodontic force in rat OTM experiments. They also reported that application of a compressive force to human PDL cells induced G1 arrest and caspase 8 protein production in human PDL cells. McCulloch et al. (1989) and Kobayashi et al. (1999) reported that cell death by apoptosis occurred following cell proliferation in response to mechanical stress. Mabuchi et al. (2002) reported that the ratios of cell proliferation and cell death were closely related to the regeneration and reconstruction of PDL in response to orthodontic force. Therefore, the rate of tooth movement may be involved in the ratios of cell proliferation and cell death of PDL cells. Furthermore, TNF‐α plays a significant role in the control of proliferation, differentiation, and apoptosis. TNF‐α has been shown to trigger apoptosis in osteoblast and PDL cells. Sugimori et al. (2018) concluded that micro‐osteoperforations may accelerate tooth movement through activation of cell proliferation and apoptosis of PDL cells.
These present and previous findings suggest that activation of inflammation, apoptosis, and cell cycles of PDL may potentially increase the rate of tooth movement.
Response of the dental pulp to mechanical forces
The dental pulp is a highly vascularized tissue situated in an inextensible environment surrounded by rigid dentin walls. The pulp vascular system is not only responsible for nutrient supply but also contributes actively to the pulp inflammatory response and subsequent regeneration (Rombouts et al., 2017).
Periodontal and pulpal blood flow increased by rat experimental tooth movement (Kvinnsland et al., 1989) and humans (Sabuncuoglu and Ersahan, 2015). Furthermore, the expression of HIF‐1α and VEGF was enhanced by mechanical force. HIF‐1α and VEGF may play an important role in retaining the homeostasis of dental pulp during OTM (Wei et al., 2015)
Römer et al. (2014) showed the induction of hypoxia in dental pulp after OTM. The induction of oxidative stress in human dental pulp cells showed up‐regulation of the proinflammatory and angiogenic genes Cox‐2, VEGF, IL‐6, and IL‐8. It suggests that OTM affects dental pulp circulation by hypoxia, which leads to an inflammatory response inside treated teeth.
Recent studies reported that an orthodontic force mediated the IL‐17 level in the dental pulp microenvironment (Yu et al., 2016). Therefore, pulp tissue may be expected to undergo a remodeling process after tooth movement.
Figure 4.4 Immunohistochemical staining for CGRP in cat PDL after canine retraction. (a) Control; (b) seven days after tooth movement in tension side; (c) seven days after tooth movement in compression side; (d) 28 days after tooth movement in tension side; (e) 28 hours after tooth movement in compression side.
(Source: Courtesy of Dr. Ze’ev Davidovitch.)
Neuropeptide response in dental pulp to orthodontic force
The innervation of the dental pulp includes sensory nerve fibers, which may also subserve dentinal fluid dynamics and regulate pulpal blood flow, providing reflexes to preserve dental tissues and promote wound healing. The main neuropeptides associated with these functions include SP, CGRP, and NKA, which are abundant in the pulp and periodontium (Kim, 1990; Ohkubo et al., 1993). Release of these neuropeptides after stimulation of sensory nerve fibers induces vasodilatation and increases vascular permeability, a condition referred to as neurogenic inflammation (Fristad et al., 1997). It is concluded that the stimulation of sensitive teeth may induce pulpal changes such as induction of neurogenic inflammation and alteration of pulpal blood flow.
The morphology and distribution of CGRP and SP through immunoreactive nerves have been shown to change their pattern as a result of local pulp trauma, indicating their role in the inflammatory process in connection with tissue injury and repair. The expressions of SP, CGRP, and NKA in inflamed human dental pulp tissue are significantly higher compared with healthy pulp. In addition, it was observed that the expression of CGRP and/or SP increases in the dental pulp in response to orthodontic treatment in rats, cats, and humans (Parris et al., 1989; Kvinnsland and Kvinnsland, 1990; Norevall et al., 1998). Another report suggested that these neuropeptides might be involved in inflammation of the dental pulp at the time of OTM (Norevall et al., 1995). Previous immunohistochemical studies demonstrated that MMP‐1, 3, 8, 9, and tissue‐type plasminogen activator expressions were significantly higher in the inflamed pulps than in clinically healthy pulps. These mediators may play an important role in the pathogenesis of pulpal inflammation.
Yamaguchi et al. (2004) reported that SP and CGRP stimulated the production of IL‐1β, IL‐6, and TNF‐α in human dental pulp fibroblasts (HDPF) in vitro. Moreover, Kojima et al. (2006) reported that SP significantly stimulated the production of PGE2 and RANKL by HDPF cells, and the increase of RANKL caused by SP stimulation in HDPF cells were partially mediated by PGE2. Shimizu et al. (2013) demonstrated that the immunoreactivity for Th17, IL‐17, IL‐17R, IL‐6 and KC (IL‐8 related protein in rodents) in the atopic dermatitis group was found to be increased in the dental pulp tissue subjected to the orthodontic force on day 9. The atopic dermatitis patients increased the release of IL‐6 and IL‐8 from human dental pulp cells. Taken together, these findings and our results suggest that HDPF may be actively involved in the progress of inflammation in the pulp tissue during OTM.
