of vasoactive peptides from the nerve endings. As previously mentioned, this hypothesis is also supported by the recent discovery of the role of DAMPs in the genesis of inflammation in response to tissue stress or damage (Chen and Nunez, 2010), which can comprise mechanical distortion and hypoxia resulting from orthodontic force application. The vasodilatation produced leads to plasma exudate formation, and migration of leukocytes out of the capillaries. In parallel, inflammatory mediators are essential to generate the local signals that confer specificity to the diapedesis and chemotaxis processes. The leukocytes that then occupy the extravascular space in the involved tissues release cytokines and growth factors to stimulate PDL and bone remodeling (Figure 4.1).
Inflammatory mediators in OTM
The transduction of mechanical forces to the cells triggers a biological response that has been described as an aseptic inflammation because it is mediated by a variety of inflammatory cytokines and does not represent a pathological condition. In contrast to chronic inflammatory responses, in which persistent stimuli sustain a long‐lasting inflammatory response and result in tissue damage, the expression of inflammatory mediators after orthodontic force application is transitory and essential for orthodontic movement, as anti‐inflammatory drugs are capable of blocking tooth movement. The concept of aseptic inflammation was recently strengthened by discovery of the DAMPs system, where endogenous molecules are able to trigger inflammatory response by cellular stress or damage through the binding of toll‐like receptors (TLRs) and nod‐like receptors (NLRs) (Chen and Nunez, 2010). This tissue response initially involves vascular changes, followed by the synthesis of prostaglandins, cytokines, and growth factors. Finally, such mediators are believed to activate tissue remodeling, characterized by selective bone resorption or deposition in compression and tension regions of the PDL, respectively (Garlet et al., 2007). Various inflammatory mediators, identified to date, associated with OTM, are summarized in Table 4.2.
Table 4.2 Inflammatory factors from PDL in response to OTM.
| In vitro studies (stimulated by mechanical stress) | In vivo studies |
|---|---|
| Prostaglandin E2 (PGE2) | Prostaglandin E2 (PGE2) |
| cAMP | cAMP, cGMP |
| IL‐1β | IL‐1α |
| IL‐6 | IL‐6 |
| TNF‐α | |
| RANKL | RANKL |
| MMP‐1, 2 | MMP‐1, 2, 3, 8, 9, and 13 |
| CGRP and SP |
DAMPs
Inflammation is usually defined as a complex biological response to harmful stimuli aimed to protect or to restore the homeostasis of a given organism. Considering that the inflammatory process is generally associated with infectious conditions, the term aseptic (or sterile) inflammation was created to describe specifically the responses generated by trauma, damaged cells, or irritants in the absence of any microorganisms. Indeed, the recent discovery of the DAMPs system rejuvenated the concept of aseptic inflammation, which has gained increasing attention from the scientific community in recent times (Chen and Nunez, 2010; McDonald et al., 2010). The DAMPs comprise a series of endogenous molecules (previously called “danger patterns,” “alarmins,” or “endokines”) released upon cellular stress, injury, or tissue damage and are capable of triggering an inflammatory response and mediate tissue repair (Chen and Nunez, 2010). DAMPs’ effects are mediated by their binding to pattern recognition receptors (PRRs), such as the TLRs or NLRs. While the PRRs were originally identified as responsible for the microbial detection, the discovery of DAMPs/PRRs binding provided a key molecular basis to understand the trigger behind aseptic inflammatory response (Chen and Nunez, 2010; McDonald et al., 2010).
As examples among DAMPS studied so far, HMGB1 (high mobility group box 1) and HSPs (heat shock proteins) have been identified in tissues after orthodontic force stimulation. HMGB1 is a protein present in the nucleus of all mammalian cells, responsible for structural and transcriptional activities, but HMGB1 is released upon cellular stress/damage by almost all nucleated cells (Goodwin and Johns, 1977; Bonaldi et al., 2002). It was recently demonstrated that HMGB1 is released by PDL fibroblasts in vivo during orthodontic movement (Wolf et al., 2013). Once secreted, HMGB1 can trigger the production of inflammatory and osteoclastogenic cytokines by PDL cells (Kim et al., 2010), and mediate their proliferation and migration (Chitanuwat et al., 2013). In addition to HMGB1, the HSPs comprise another class of DAMPS, possibly related to inflammation associated with the OTM. It was demonstrated that HSPA1A and HSPB1 are upregulated in PDL at an early stage of tooth movement (Arai et al., 2010; Baba et al., 2011). Like HMGB1, HSPs can act as a trigger for inflammatory reaction to orthodontic forces during the early stages of tooth movement. Accordingly, unpublished data from our group (Garlet laboratory) demonstrate that HMGB1 and HSP levels are upregulated even before the increase in first‐messengers expression (i.e., IL1beta and TNF‐alpha), reinforcing its potential role as trigger of the inflammatory reaction. Accordingly, recent studies demonstrate that the application of orthodontic forces upregulates HMGB1 expression in rat periodontal tissue in a time‐ and force‐dependent manner ( Wolf et al., 2014a, b; Zou et al., 2019). It is also important to mention that both HMGB1 and HSPs are produced in response to hypoxia (Oettgen, 1990; Hendrick and Hartl, 1993), a condition characteristically present in the PDL area during orthodontic movement. Therefore, DAMPs are potentially the trigger of the inflammatory reaction in response to orthodontic forces, as well in the subsequent reparative events that lead to tissue remodeling. It is also important to consider that DAMPs can act as triggers and regulators of inflammatory response. Recent studies demonstrate that HSP production by PDL cells, triggered by mechanical loading, can dampen the subsequent inflammatory response, suggesting the existence of auto‐regulatory mechanisms that limits the inflammatory process (Marciniak et al., 2019; Wolf et al., 2016). Importantly, DAMPs (such as HMGB1) can also exert direct anabolic effects on PDL cells, suggesting that its involvement in OTM can be extended beyond its proinflammatory properties (Wolf et al., 2014a, b).
Prostaglandins
Prostaglandins (PGs), products of arachidonic acid metabolism, are local, hormone‐like chemical agents produced by mammalian cells including osteoblasts that are synthesized within seconds following cell injury. One of the derivatives of the arachidonic acid cascade, PGE2, acts as a vasodilator by causing increases in vascular permeability and chemotactic properties, and also stimulates the formation of osteoclasts and an increase in bone resorption. The cyclooxygenase (COX) family of enzymes consists of two proteins that convert arachidonic acid, a 20‐carbon polyunsaturated fatty acid comprising a portion of the plasma membrane phospholipids of most cells, to PGs. The constitutive isoform (COX‐1) is found in nearly all tissues and is tissue protective. In contrast, COX‐2, the inducible isoform of COX, appears to be limited in basal conditions within most tissues, while de novo synthesis is activated by cytokines, bacterial lipopolysaccharides, or growth factors, to produce PGs in large quantities in inflammatory processes. There are several lines of evidence showing that COX is also closely associated with periodontitis, and that PGs are mediators of gingival inflammation and alveolar bone resorption (Offenbacher et al., 1993).
With
