Читать книгу Biological Mechanisms of Tooth Movement - Группа авторов - Страница 57

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).