This increased permeability, with additional signals that confer chemotaxis specificity (provided by a class of chemotactic cytokines, collectively called chemokines), allows the migration of cellular components of blood from the lumen of the vessels into the extracellular spaces within the surrounding tissue. Once in the tissue, the cells follow a chemotactic gradient generated by the interaction of chemokines with the extracellular matrix, directing their migratory process. The migration of the leukocytes from the blood vessel lumen is also accompanied by secretion of exudates from the capillaries. There are a number of biochemical substances known to mediate cell migration‐associated changes, such as histamine, leukotrienes, prostaglandins, cytokines, and chemokines.
An inflammatory response is essential in the remodeling of alveolar bone and PDL during OTM. Researchers have been able to demonstrate histological and vascular changes in the PDL, as well as in the alveolar bone following inflammation associated with orthodontic force application (Table 4.1) (Storey, 1973; Kvinnsland et al., 1989). Biological factors, such as different classes of cytokines, chemokines, neurotransmitters, and genes implicated in the process and its associated increase in periodontal tissues of mechanically stressed teeth have been identified (Vandevska‐Radunovic, 1999). At this point, it is didactically possible to consider some of these molecules as the molecular triggers of host response (i.e., the first mediators produced in response to mechanical stimulation/damage of cells and tissues), which will subsequently lead to the development of a cascade pathway, mediated by effector molecules (also called first messengers). The first messengers will continue, sustain and/or amplify the inflammatory response by means of second messengers’ activation, which will ultimately be responsible for the cellular/tissue response and/or outcome. Recent evidence points to endogenous molecules, collectively named DAMPs, as the potential molecular triggers of the inflammatory process after orthodontic force application. In this context, both mechanical distortion of PDL cells and blood flow alterations subsequent to orthodontic force application could trigger DAMPs release, which in turn would elicit the subsequent first to second messengers cascade that ultimately leads to inflammation development.
Table 4.1 Difference in response of PDL and alveolar bone to light and heavy forces.
| Time | Light pressure | Heavy pressure |
|---|---|---|
| < 1 s | PDL fluid compressible, alveolar bone bending leading to release of signals. (Piezoelectric and streaming potentials.) | PDL fluid compressible, alveolar bone bending leading to release of signals. (Piezoelectric and streaming potentials.) |
| 1–2 s | PDL fluid expressed and tooth movement occurs utilizing PDL space. | PDL fluid expressed and tooth movement occurs utilizing PDL space. |
| 3–5 s | PDL cells and fibers are mechanically distorted. Blood vessels will become partially compressed on pressure side and dilated on tension side. | PDL blood vessels on pressure side become occluded. |
| Minutes | Blood flow is altered leading to changes in PO2 (partial pressure of oxygen). Release of first messengers (prostaglandins and cytokines). | Blood flow cut off due to excessive pressure. |
| Hours | Metabolic changes, enzyme release, release of second messengers leading to rapid cellular activity. | The compressed area shows signs of cell death (necrosis and hyalinization). |
| Approx. 4 hours | Increase in level of second messengers (cAMP and others). Increased cellular differentiation within PDL. | Cellular differentiation occurs in adjacent unaffected areas. Beginning of undermining resorption. |
| Approx. 2 days | Tooth movement begins as bone remodeling progresses. | Continuing undermining resorption. |
| 7–14 days | Undermining resorption removes lamina dura adjacent to PDL and tooth movement occurs. |
Proinflammatory cytokines, such as interleukin‐1 (IL‐1) and tumor necrosis factor‐α (TNF‐α), have been shown to be involved in the cascade pathways to elicit acute and chronic inflammation. These cytokines are also involved in bone remodeling (Davidovitch et al., 1988). Literature regarding this suggests that peripheral nerve fibers and neurotransmitters are involved with the inflammatory process and bone remodeling. Mediating substances in neurogenic inflammation such as calcitonin gene‐related peptide (CGRP) and substance P (SP), have also been proposed to be involved with many inflammatory processes like vasodilatation, increased microvascular permeability, production of exudate, and increased proliferation of endothelial cells and fibroblasts (Vandevska‐Radunovic, 1999).
Different types of neurotransmitters have also been shown to contribute either directly or indirectly to the regulation of osteoblasts and osteoclasts. These neurotransmitters include: CGRP, SP, vasoactive intestinal polypeptide (VIP) and nitric oxide. The various neurotransmitters are synthesized within the ganglion sensory cells before being distributed throughout the central and peripheral nervous system. Release of these neurotransmitter substances is stimulated by the activation of mechanoreceptors or nociceptors (Nicolay et al., 1990). These neurotransmitters then help in generating cyclic adenosine 3´,5´‐monophosphate (cAMP) and inositol triphosphate (IP3), which act as second messengers within the cells (Sandy et al., 1993). The intracellular second‐messenger molecules transmit their signals to the nucleus via a series of enzymatic reactions. The stimulated nucleus synthesizes the immediate early genes (IEG), depending on the differing signals received. These IEGs have been identified as c‐fos, c‐jun and egr‐1. The IEGs are eventually translated into activator protein‐1 (AP‐1), which is a transcription factor that modulates the activity of the gene to which it binds, the effect of which is to produce proliferation or differentiation of the cells (Dolce et al., 2002).
Increased blood vessel dilation and permeability are necessary components of the inflammatory process and are therefore involved with bone remodeling. Migration and chemotaxis of leukocytes extravasated from the blood vessel lumens are also necessary processes in bone remodeling (Davidovitch et al., 1988). The converse is also true. Any inhibition of leukotriene or prostaglandin synthesis will inhibit inflammation and bone remodeling. Monocytes, lymphocytes, and mast cells have been shown to express neuropeptide receptors on their cell surfaces, and therefore it has been postulated that CGRP and SP may have a direct influence on the inflammatory process. With this evidence in hand, the peripheral nervous system has been proposed to act as a link between physical stimuli and biological responses in tooth movement.
Figure 4.1 Initial effects of orthodontic forces on paradental tissues.
The hypothesis proposed by Davidovitch et al. (1988) suggests that the mechanical stress, which distorts the cells and matrix of the paradental tissues, imparts strain to
