**7.1.** *IL-1β***,** *IL–6***, and** *TNF-α* **and remodeling (resorption and apposition) of bones**

The effects of *IL-1β*, *IL–6,* and *TNF-α* during the orthodontic tooth movement are going in a few connected directions and occur within the physiological process of remodeling of periodontal tissue after the application of mechanical forces. Judging by their concentration in gingival fluid, the creation of all three interleukins is already increased at the beginning stage of this process (12th and 24th hour) when leukocytes and fibroblasts of gingiva, periodontal ligament and alveolar bone make them as mediators of inflammation due to forces [6, 18, 23]. The maximum level is reached on the third day after the application of these forces [23].

*IL-1β*, *IL–6*, and *TNF-α* are osteotropic cytokines. They are released at the inflammatory spot and directly or indirectly (via substances whose synthesis and excretion they influenced) react with bone cells initiating the process of bone resorption [16]. Generally, it is believed that the bone resorption caused by inflammation is caused by local stimulation of osteoclast initiated by the effects of cytokines released from the infiltrated inflammatory cells [24, 25]. The process occurs in a complex signal manner via receptors of *TNF–α* (*TNF–R1*) at osteoblasts [24]. This receptor is activated by nuclear transcription factor *NF-κB*, so it is therefore called receptor activator of *NF-κB* ligand (*RANKL*) [26]. *RANKL* binds itself for the receptor at mature osteoclasts called *RANK*. Binding itself for *RANK*, *RANKL* may activate mature osteoclast and their precursors in the direction of oclastogenesis. It is prevented from doing so by natural antagonist osteoprotegerin (OPG), soluble receptor bait for RANKL, which prevents its binding for *RANK*, acting as a natural inhibitor of maturation and activation of osteoclast [27, 28]. For *TNF–α* and IL*-1β*, it is shown that together or independently from one another, *IL-1β* via *IL-1RI* receptors at osteoblasts may regulate the balance between *RANKL* and *OPG* in microenvironment of bones and mesenchymal tissue along the bone [29], not only intensifying the expression of *RANKL* and contributing to the resorption of bones, but also that they may activate osteoclasts at RANKL independently [30]. There is evidence that *IL-1β* and *IL-6* released by osteoclasts themselves may cooperate with pro-inflammatory *IL-1β* and IL-6 in osteoclastogenesis [31].

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*, as well as the level of these cytokines in gingival fluid is decreased after 7–10 days since the beginning of the effect of mechanical forces [18, 23], which overlaps with the initial phase of reparation of periodontal tissue, which lasts for approximately 9 days [31]. During this stage, blood vessels are no longer excessively permeable [32]. In this stage the creation of transforming growth factor beta is intensified (TFG-β), insulin-like growth factor (IFG I and II), fibroblast growth factor (FGF), IL-10, etc. [33], which modulate the reactivity of osteoblasts and prevent the bone resorption [31]. Complicated interactions among these factors, with many of them still not being explained entirely, create the basis of the coordinated formation of a new bone at the resorption location.

#### **7.2.** *IL-1β, IL-6,* **and** *TNF-α* **and orthodontic forces**

forces, is attributed to cytokines [6]. 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

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 sys-

temic 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**

**7.1.** *IL-1β***,** *IL–6***, and** *TNF-α* **and remodeling (resorption and apposition) of bones**

The effects of *IL-1β*, *IL–6,* and *TNF-α* during the orthodontic tooth movement are going in a few connected directions and occur within the physiological process of remodeling of periodontal tissue after the application of mechanical forces. Judging by their concentration in gingival fluid, the creation of all three interleukins is already increased at the beginning stage of this process (12th and 24th hour) when leukocytes and fibroblasts of gingiva, periodontal ligament and alveolar bone make them as mediators of inflammation due to forces [6, 18, 23]. The maximum level is reached on the third day after the application of these forces [23].

*IL-1β*, *IL–6*, and *TNF-α* are osteotropic cytokines. They are released at the inflammatory spot and directly or indirectly (via substances whose synthesis and excretion they influenced) react with bone cells initiating the process of bone resorption [16]. Generally, it is believed that the bone resorption caused by inflammation is caused by local stimulation of osteoclast initiated by the effects of cytokines released from the infiltrated inflammatory cells [24, 25]. The process occurs in a complex signal manner via receptors of *TNF–α* (*TNF–R1*) at osteoblasts [24]. This receptor is activated by nuclear transcription factor *NF-κB*, so it is therefore called receptor activator of *NF-κB* ligand (*RANKL*) [26]. *RANKL* binds itself for the receptor at mature osteoclasts called *RANK*. Binding itself for *RANK*, *RANKL* may activate mature osteoclast and their precursors in the direction of oclastogenesis. It is prevented from doing so by natural antagonist osteoprotegerin (OPG), soluble receptor bait for RANKL, which prevents its binding for *RANK*, acting as a natural inhibitor of maturation and activation of osteoclast [27, 28]. For *TNF–α* and IL*-1β*, it is shown that together or independently from one another, *IL-1β* via *IL-1RI* receptors at osteoblasts may regulate the balance between *RANKL* and *OPG* in microenvironment of bones and mesenchymal tissue along the bone [29], not only

change of the gene expression in them.

40 Current Approaches in Orthodontics

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 *IL-1β*, *IL–6*, and *TNF-α* is increased both in the zone of compression and in the zone of tension (in comparison with the control teeth), but the level of some of them in either of these zones is different [34, 35]. It is believed that these differences are the reflection of specificity of the process, which occurs at the location of effect of certain force during the orthodontic treatment [34]. Even though they are not completely harmonized, the data so far show that the level of pro-inflammatory cytokines in comparison with control teeth is generally higher in the compression zone than in the tension zone, which is connected to the role of these cytokines in the regulation of osteoclastogenesis mediated by RANKL (vide supra) and the process of bone resorption at the compression spot [34, 35]. Simultaneously, it is shown that the expression of anti-inflammatory cytokine *TGF-β* is greater at the tension spot than at the compression spot, which is attributed to its role in the process of inhibition of osteoclastogenesis and bone formation at the tension spot [35]. However, the balance between pro-inflammatory and antiinflammatory mediators at the spots of compression and tension is still not studied enough.

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 (*IL-1β*, *TNF-α*) and anti-inflammatory (*IL-4, IL-10, TGF*-*β*) cytokines, which are created during the resorption and reparation of bones [36]. At the experimental model (rat), it was noticed that after the application of the orthodontic force iONS is the mediator in the bone resorption caused by the inflammation at the compression zone and eNOS in the bone creation at the tension zone [37].

growth factor (NFG), which then leads to the increased production of SP and CGRP, which establishes the mechanisms of positive feedback during the inflammatory response [41].

Apart from mutual interactive effects in the processes of inflammatory responses and bone remodeling during the orthodontic tooth movement, *IL-1β, IL-6*, and *TNF-α* frequently have effects in the combination with various other bioactive structures included in these

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 *IL-8* in gingival fluid [6, 45], which is known to regulate inflammatory responses in periodontium in combination with other cytokines [46]. *IL-1β, IL-6,* and *TNF-α* stimulate the creation of *IL-8* in monocytes, macrophages, epithelial cells, and fibroblasts of periodontium, so that the IL-8 mechanism of feedback could initiate the creation of *IL-1β, IL-6*, and *TNF-α* [6], when periodontal system moves from resorptive to formative stage of bone remodeling. With IL-8 during the orthodontic treatment, the level of IL-2 also increases and it is considered to be the

The increased expression of pro-inflammatory cytokines in human periodontium, due to

This prostaglandin, which is created in various cells of mammals as one of the intermediary products of metabolism and arachidonic acid, is the mediator in the sustaining of local homeostasis, modulating numerous physiological processes including the inflammation. During the resorptive phase of bone remodeling caused by mechanical stress and initiated

cally deformed osteoblasts and gingival fibroblasts), stimulating the creation of osteoclasts, which intensifies the bone resorption [16]. In this process, *IL-1β* and *TNF-α* express synergistic

inflammatory cytokines [48] and, consequently, the inhibition of the inflammatory response

and bone formation on the other) is interpreted by the possibility of prostaglandin directing in different manners the bone cells: for resorption those in bone marrow and for the bone

The inflammatory response, which occurs during the orthodontic tooth movement, is fol-

occurs in soluble form in different bodily fluids of organisms including the gingival fluid and also is in the composition of the main histocompatible locus of I class (MHC class I), which is expressed at the surface of various cells, mostly lymphocytes and monocytes. In the process

expression, microglobulin (β<sup>2</sup>

with the pro-inflammatory cytokines initiate the process of bone remodeling [18]. β<sup>2</sup>

is created in cells of periodontal ligament (mechani-

The Role of Cytokines in Orthodontic Tooth Movement http://dx.doi.org/10.5772/intechopen.80078

(resorption on the one hand


stimulating the fibroblasts to the synthesis of this prostaglandin.

in the reaction results in the decrease of the expression of pro-

 (*PGE2 )*. 43


orthodontic forces, is followed by prominent increase in the level of prostaglandin E<sup>2</sup>

**7.4.** *IL-1β, IL-6,* **and** *TNF-α* **and other inflammatory mediators in periodontium**

indicator of inflammatory activities in periodontium [47].

and stimulation of the bone formation. This dual role of *PGE2*

by acute inflammatory response, *PGE2*

effects to the creation of *PGE2*

The increased level of *PGE2*

formation those at their surface.

lowed by the increase of β<sup>2</sup>

processes.

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* from the pulp fibroblast, which results in its inflammation [17]. The process is specifically related to the pulp innervations and neurogenic mechanisms [38], and in the case of more expressed effect of mechanical forces may lead to the resorption of the tooth root [39].
