One of the most important breakthroughs in the understanding of biological features of bones is the explanation of the role of cytokine in reshaping of the bone (remodeling) including the alveolar tooth bone exposed to the effect of the mechanical force during the orthodontic treatment. Since remodeling of the bone initiated by orthodontic forces is connected during its early stage with the inflammation of the surrounding tissue, the assumption was presented about the role of the pro-inflammation cytokine in the process of remodeling of the bone, primarily IL-1β, IL-б, and TNF. These cytokines are mediators in the reactions of the acute stage of inflammation, as well as in the processes of metabolism, stimulation of resorption, and inhibition of bone creation. In this chapter, we aimed to review the existing knowledge about the roles and dynamics of the change in these three cytokines simultaneously during the early stage of the orthodontic tooth movement.
- orthodontic tooth movement
- reshaping of bones
When more than 100 years ago the world knew about the theory about the regulation of the tooth movement, cytokines were unknown to science . The first experimental evidence that supported the assumption about cytokines being the potential regulators of the reshaping process (remodeling) of bones during the orthodontic treatment was obtained approximately 20 years ago . Since then, until today, the efforts of researchers last in order to clarify molecular events with cytokines as mediators, which follow the orthodontic tooth movement.
The role of cytokines in the orthodontic tooth movement is considered in the context of inflammation, which occurs at the very beginning of this process as a reaction to the mechanical pressure and represents necessary precondition for the realization of all its subsequent levels. In the conjunction of mechanical and biological mechanisms, which move the teeth during the orthodontic treatment, cytokines are given great importance for their feature of transmission of biochemical signals among numerous cells of various kinds reacting to orthodontic forces. Binding themselves to specific receptors at membranes of these cells, cytokines cause in them the biochemical changes responsible for the signal transmission to corresponding genes in these cells and, consequently, to the change of gene expression in them. This orthodontic tooth movement causes the features of unusually complex processes, whose different degrees—each individually and all together—are regulated by the network of positive and negative feedbacks, in which cytokine molecules act as mutual activators or inhibitors .
2. Orthodontic tooth movement and force effect
Orthodontic tooth movement is a biomechanical process initiated by the effect of mechanical forces, which overpower the bio-elasticity of the support tissue .
The process of orthodontic movement of teeth is based on the transformation (remodeling) of periodontal tissues and is initiated by external forces and differs from the processes that occur during normal jaw function (dentition, chewing) . On the basis of remodeling of periodontium, there are mechanisms, which transform the physical effort into various cell responses within the periodontal system, which primarily leads to the disturbance and then to the establishment of the periodontal homeostasis on a different basis . These mechanisms provide the adaptation of the biological system of periodontium to the changed conditions emerged as a result of the effect of orthodontic forces.
Biomechanical mechanisms of the orthodontic tooth movement, because of their complexity, have been explained by various, but not mutually exclusive theories. Orthodontic dogma is considered to be the one according to which the movement of the tooth in the periodontal space occurs by the effect of two dominant forces: pressure force (compression) and tensile strength (tension) . As a result of the pressure, there is resorption (suction), whereas as a result of tension to apposition (addition) of alveolar bone, the movement of the tooth occurs as a direct outcome of the reshaping of the tissue around the tooth root caused by forces. On basis of this, processes are vascular, and consequently, cellular changes of the dental tissue are caused by chemical mediators, which are created and released under the influence of orthodontic forces. Even though, in the context of this, we must not neglect the theory, which emphasizes bending of the bones as the basis of the orthodontic tooth movement , as well as the theory of bioelectrical signals, which emphasizes the importance of electric potentials, which are created in the tissue as a response to the application of the mechanical force .
Orthodontic forces lead to the change of the structural features of dental tissues at the level of cells, molecules, and genes. Mutual activities of tooth cells, periodontal ligament, bone, and bioactive substances (cytokine, chemokine, hormone, growth factor, enzymes, neuropeptides, and ligands) are necessary because they provide that during these changes, the tooth and periodontal ligament remain clinically intact and surrounding bone is reorganized. The final outcome of these activities (the speed of orthodontic movement of teeth) may be defined as a phenotypic expression of numerous gene-controlled mechanisms, which connects the orthodontic tooth movement with hereditary basis, i.e., hereditary variations of factors which participate in this process .
3. Orthodontic tooth movement and biological mechanisms of reshaping of the mechanic-sensitive dental tissue
The cells of alveolar bones and periodontal ligament, gingiva, and tooth pulp react to the effect of orthodontic forces after the remodeling of extracellular matrix (ECM), which surrounds them . Dental and periodontal cell responses to the applied mechanical force comprise interactions of intracellular and extracellular structural elements and mutual influences of the effects of various biochemical structures. The nature of changes in the process of reshaping is determined by the combinatory of interactions, which is different at different levels of the tooth movement . The scheme no. 1 presents the main events in dental tissues, which follow orthodontic movement of the tooth.
4. Orthodontic tooth movement and the change in the structure of cytoskeleton
The function of all cells in mechanic-sensitive dental tissues is closely related to the ECM, which surrounds them and makes the corresponding microenvironment for cell activities, which emerge after the application of orthodontic force. The orthodontic treatment leads primarily to ECM periodontium deflection, which results in the changes of cytoskeleton structure of cells anchored in ECM. ECM is multicomponent tissue, which enables the transmission of mechanical signals to the corresponding cells and thus the occurrence of changes in the structure and function of a certain tissue . The structural components of ECM (collagen, fibronectin, laminin, elastin, proteoglycans, hyaluronic acid, etc.) bind with the adhesive receptors at cells called integrins, via which the mechanical stimuli are transmitted into the cell causing the changes of cytoskeleton structures. The application of mechanical force outside disturbs the integrin receptors at fiber areas of periodontal ligament and gingiva and bone cells (osteoblast, osteoclast, osteocytes), and their adaptive response may increase or decrease the creation of integral elements of ECM in them and thus influence the change of the mass and morphological appearance of the bone .
5. Orthodontic tooth movement and reorganization of blood vessels
Blood vessels in periodontal ligament actively participate in the remodeling of dental tissues, which is related to the orthodontic tooth movement. Under the influence of mechanical forces, the reshaping of existing and creation of new blood vessels at periodontal ligament occur. These processes occur via numerous signal paths, which are activated after the deflection of ECM, which surrounds the cells of endothelia of blood vessels. They are mostly established via integrin of endothelial cells and ECM structures, which surround the blood vessels  and lead to the organization of endothelial cells unto multicellular pre-capillary network . The response of blood vessels of periodontal ligament to the effect of mechanical forces is expressed by increased permeability, which, on its side, increases the fluid outpouring from capillary into the interstitial space . These blood vessels play an essentially important role in aseptic inflammatory reaction caused by mechanical forces, acting as a source of inflammation mediators (cytokine and neurotransmitters), which mutually react with endothelial cells of periodontal capillary network encouraging them to bind circulating leukocytes and influence their relocation into periodontal ECM.
6. Orthodontic movement of teeth and inflammation
The mechanical stimulus stemming from the orthodontic forces causes aseptic inflammatory reaction within periodontal tissues, which initiates biological processes, which are connected to the reshaping of the bone . Even though in normal conditions the movement of teeth is a sterile process, the early stage of orthodontic tooth movement is observed as a type of tissue injury and it is accompanied by the acute inflammatory response.
Generally speaking, the acute inflammation is an initial stage of defense reaction of the mechanism to the tissue injury (mechanical, physical, chemical, nutritive, biological). It occurs fast and does not last long and it emerges as the result of numerous, complex, and mutually related processes via which certain proteins and cells are transmitted from blood to the damaged tissue and whose final result is the recovery of the tissue. The acute phase of the inflammation is characterized by vascular changes (vasodilatation and increased permeability of blood vessels) and consequently, plasma leakage (exudation) and relocation of leukocytes (extravasation) from blood into the injured tissue.
Immediately upon the application of orthodontic force, the disturbance of the microcirculation of periodontal ligament occurs, which results in the ischemia of local tissue, periodontal vasodilatation, and migration of leukocytes via capillaries of periodontal ligament. The changes are temporary and, by the rule, do not have pathological effects.
Even though inflammatory changes occurred during the orthodontic tooth movement are mostly the consequence of reactive processes in the support tissue, mechanical stimuli may be transmitted also to the tooth pulp and may initiate the inflammatory response within this dental tissue .
6.1. Orthodontic movement of teeth and inflammation mediators
Inflammatory response in orthodontic tooth movement is followed by the increased creation of inflammatory mediators (cytokines, prostaglandins, leukotrienes), enzymes (matrix metalloproteinase, lactate-dehydrogenase, alkaline phosphatase, aspartate-aminotransferase), growth factor (epidermal growth factor—EGF), and neuropeptides (P-SP substance, calcitonin gene-related peptide—CGRP), which indicates the participation and mutual communication of cells of immune, endocrine, and nervous system in the regulation of the bone remodeling [16, 18, 19, 20, 21, 22].
The primary role in the initiation of a series of biochemical processes that stimulate or inhibit cellular activities during the inflammatory changes, initiated by the effect of orthodontic forces, is attributed to cytokines . Cytokines are small protein molecules, which transmit signals among cells. They are excreted by various cells as a response to external stimuli, and most frequently, they have a local effect. The effect of cytokines may be autocrine (to the cell which excretes it), paracrine (to other, adjacent cells), and endocrine (to distant cells). Cytokines express their effects by binding themselves to specific receptors at the cell membrane, which are affected by cytokines causing the biochemical changes responsible for the transmission of the signal to the corresponding genes in these cells and, consequently, to the change of the gene expression in them.
During the orthodontic tooth movement, cytokines are created by the inflammatory cells, which after the mechanical stimulus came outside widened capillaries of periodontal ligament [6, 18]. As the main regulators of the bone remodeling process during the orthodontic treatment, three cytokines are mentioned: interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) [6, 18, 23]. All three cytokines cause many local and systemic changes, which are the features of the acute stage of inflammation (Figure 1).
7. Orthodontic tooth movement and
IL-1β, IL–6, and TNF-α effects
IL-1β, IL–6, and TNF-α and remodeling (resorption and apposition) of bones
The effects of
The termination of the resorption of bones and initiation of its reformation comprises inhibition of the osteoclast function and stimulation of the activity of osteoblasts. The termination of resorption cycle includes the inhibition factors, which are created not only by surrounding cells but also by the osteoclasts themselves. They regulate negatively the activity of these cells causing their apoptosis and preventing their creation and simultaneously increasing the function of osteoblasts. This stage of normal bone remodeling is followed by lowering of the level of pro-inflammatory cytokines. The number of cells of inflammation, which are created by
IL-1β, IL-6, and TNF-α and orthodontic forces
Although the causal relationship of cytokine expression and orthodontic force is not entirely explained, it is believed that the direction and the nature of these forces affect the level of changes in the blood flow and thus the relationship of inflammatory mediators, which are expressed in periodontal tissues and gingival sulcus. The blood flow is decreased at the spot of compression (ligament compression) and increased at the spot of tension (ligament stretching); therefore, the response of the tissue at this location is greatly determined by the opposing forces that affect them. The inflammatory reaction occurs in both spots and the content of
The effects of cytokine in the response of the tissue to orthodontic forces are connected to the creation of nitrogen oxide (NO), which is known to be one of the important regulators of bone remodeling. For the creation of NO, the activity of two enzymes is necessary: inducible nitrogen-oxide synthesis (iNOS) and endothelial nitrogen-oxide synthesis (eNOS). The gene expression of these two enzymes is activated by pro-inflammatory (
Orthodontic forces express their effect to the dental pulp initiating the responses of fibroblast in it. Even though it is considered that the reactions of the pulp to the orthodontic treatment are very small, they still bring about changes in the blood flow and releasing of
IL-1β, IL-6, and TNF-α and “neurogenic inflammation”
The orthodontic tooth movement is accompanied by releasing neuropeptides from peripheral endings of sensor nerves, which permeate the dental pulp and periodontium, as well as from the inflammatory cells localized in the periodontal tissue. Released neuropeptides regulate the microcirculation of the pulp and mediate in inflammatory processes during remodeling of bones, characteristic for orthodontic tooth movement . Such neural effect, which is generally called “neurogenic inflammation,” is connected to the pain, which partially occurs during stretching and pressing of the tissue under the influence of mechanical forces and partially because of the interaction of numerous inflammatory mediators with local pain receptors [38, 40].
The main mediators of neutrogenic inflammation are neuropeptides, SP and CGRP, which are proven to have vasodilatation effect, increase vascular permeability and participate in the inflammatory processes related to the damage, and recovery of the tissue . The increase of the level of these neuropeptides is recorded in gingival fluid immediately after the effect of orthodontic forces, which occurs simultaneously with the increase of the level of pro-inflammatory cytokines
The effects of neuropeptides to cytokines are not unidirectional [19, 38].
IL-1β, IL-6, and TNF-α and other inflammatory mediators in periodontium
Apart from mutual interactive effects in the processes of inflammatory responses and bone remodeling during the orthodontic tooth movement,
After the primary inflow to the inflammation location and the initiation of an early stage of periodontal remodeling, these cytokines start the second tide of cytokine regulation of this process by “introducing” other relevant cytokines. It is shown that an early but not initial phase of the orthodontic tooth movement is followed by the increase of the level of
The increased expression of pro-inflammatory cytokines in human periodontium, due to orthodontic forces, is followed by prominent increase in the level of prostaglandin E2 (
The inflammatory response, which occurs during the orthodontic tooth movement, is followed by the increase of β2 expression, microglobulin (β2-
Apart from pro-inflammatory cytokines and other pro-inflammatory substances, during the orthodontic tooth movement to gingival fluid, various metabolites are released, too. For lactate-dehydrogenase (
The damage of dental tissues caused by inflammation and its reparation are based on many elements and their coordination inside and outside cells. Even though there are differences between pathological inflammatory changes and those which accompany mechanically caused reshaping of tissues, the basic cellular responses to stimuli, regardless of their nature, express essentially the same properties . Our researches of changes of individual integral parts of the immune system and ECM in normal and inflammatory gingiva [51, 52, 53] were the basis for the examination of the expression of IL
The early stage of the tooth movement is followed by the inflammatory response of the tissue to the effects of the mechanical force, which are conducted and regulated by pro-inflammatory cytokines
The execution of this chapter was financially supported by the Ministry for Science and Technological Development of the Republic of Serbia (project no. OI175061).
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