**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, 18–22].

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 [14] and lead to the organization of endothelial cells unto multicellular pre-capillary network [11]. 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 [15]. 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

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 [16]. 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

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

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

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

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),

influence their relocation into periodontal ECM.

38 Current Approaches in Orthodontics

(extravasation) from blood into the injured tissue.

dental tissue [17].

**6. Orthodontic movement of teeth and inflammation**

injury and it is accompanied by the acute inflammatory response.

changes are temporary and, by the rule, do not have pathological effects.

**6.1. Orthodontic movement of teeth and inflammation mediators**

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

**Figure 1.** The sequence of events in dental tissues during orthodontic tooth movement. ECM—extracellular matrix; PDL—periodontal ligament.

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 change of the gene expression in them.

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

The Role of Cytokines in Orthodontic Tooth Movement http://dx.doi.org/10.5772/intechopen.80078 41

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

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.

IL-6 in osteoclastogenesis [31].

formation of a new bone at the resorption location.

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

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**).
