Osteoimmunology of Oral and Maxillofacial Diseases: Translational Applications Based on Biological Mechanisms

Abstract

The maxillofacial skeleton is highly dynamic and requires a constant equilibrium between the bone resorption and bone formation. The field of osteoimmunology explores the interactions between bone metabolism and the immune response, providing a context to study the complex cellular and molecular networks involved in oro-maxillofacial osteolytic diseases. In this review, we present a framework for understanding the potential mechanisms underlying the immuno-pathobiology in etiologically-diverse diseases that affect the oral and maxillofacial region and share bone destruction as their common clinical outcome. These otherwise different pathologies share similar inflammatory pathways mediated by central cellular players, such as macrophages, T and B cells, that promote the differentiation and activation of osteoclasts, ineffective or insufficient bone apposition by osteoblasts, and the continuous production of osteoclastogenic signals by immune and local stromal cells. We also present the potential translational applications of this knowledge based on the biological mechanisms involved in the inflammation-induced bone destruction. Such applications can be the development of immune-based therapies that promote bone healing/regeneration, the identification of host-derived inflammatory/collagenolytic biomarkers as diagnostics tools, the assessment of links between oral and systemic diseases; and the characterization of genetic polymorphisms in immune or bone-related genes that will help diagnosis of susceptible individuals.

Mucosal Immunity and the FOXO1 Transcription Factors

“…Lymphocytes play important protective and destructive roles in periodontitis (25). B-lymphocytes are the predominant leukocyte in chronic inflammatory periodontal lesions and differentiate to plasma cells that produce antibody (36).…”

Interleukin‐35 inhibits alveolar bone resorption by modulating the Th17/Treg imbalance during periodontitis

“…The hallmark of periodontitis pathogenesis is alveolar bone resorption caused by the increased activity of osteoclasts, and this increase in resorptive activity occurs by the enhanced production of RANKL elicited by Th17 lymphocytes, as a consequence of the local Th17/Treg imbalance (Alvarez et al, 2019; Campbell et al, 2016). In the present study, IL‐35 inhibited the alveolar bone resorption in periodontitis mice and this inhibition was associated with diminished osteoclast detection and downregulated RANKL expression in the periodontal lesions.…”

“…On the other hand, the detected changes in the RANKL/OPG imbalance could also involve an inhibitory effect of IL‐35 on other RANKL‐producing cells such as osteoblasts and fibroblasts, which are critical RANKL producers in several diseases whose pathogenesis is associated with the Th17/Treg imbalance (Alvarez et al, 2019; Dong, 2006; Fumoto, Takeshita, Ito, & Ikeda, 2014). In this context, an inflammatory milieu enriched in Th17‐related cytokines, such as IL‐6 and IL‐17A, may exert osteoclastogenic activity by inducing RANKL expression on osteoblasts and fibroblasts, as well as favour the recruitment and activation of other immune cells and the net increment of pro‐inflammatory and RANKL‐inducing cytokines in the periodontitis‐affected tissues (Alvarez et al, 2019; Sato et al, 2006). Interestingly, recently reported data have suggested that IL‐35 could also favour bone regeneration by inducing OPG production and osteoblast differentiation through Wnt/β‐catenin signalling (Li et al, 2019).…”

“…In this context, it has been clearly established that the activity of specific T‐lymphocyte subsets plays a key role in the pathogenesis of periodontitis, where T‐regulatory (Treg) lymphocytes are protective and T‐helper type 17 (Th17) lymphocytes are involved in periodontal inflammation and tissue breakdown (Alvarez et al, 2018; Campbell, Millhouse, Malcolm, & Culshaw, 2016). During periodontitis, the metabolic balance of tooth‐supporting alveolar bone relies on the reciprocal relationship between Th17 and Treg lymphocyte activity; in fact, pathogenic alveolar bone resorption is a consequence of the Th17/Treg imbalance in periodontitis‐affected tissues (Alvarez et al, 2019; Campbell et al, 2016).…”

Cytokines Differently Define the Immunomodulation of Mesenchymal Stem Cells from the Periodontal Ligament

“…Periodontitis is an inflammatory disease of the tooth supporting tissues that might lead to tooth loss if it remains untreated. T lymphocytes play a crucial role in periodontitis progression by contributing to osteoclast formation and alveolar bone resorption and by contributing to a pro-inflammatory environment [42]. It is also known that tissue destruction in periodontal disease is mainly caused by a dysregulated immune response.…”