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.

Keywords: biomarkers; maxillofacial; oral; osteoimmunology; periodontal disease.

Figure 1

Osteoimmunology of periodontal disease. During periodontitis, the immune response induced by the dysbiotic microbiota enhances the production of local RANKL by different immune cells types such as Th1, Th17, B cells. Additionally, the increased gingival levels of IL-17 stimulate the membrane-bound expression of RANKL in osteoblasts and periodontal ligament fibroblasts; this provokes the activation of osteoclast and bone-loss. On the contrary, in health, different immune cells such as Tregs, Bregs, M2, and Th2 cells promote an anti-inflammatory and pro-anabolic state that sustain the alveolar-bone homeostasis. PMNs, polymorph nuclear neutrophil; B/P, B and plasma cell.

Figure 2

Immunological features of active and inactive periapical lesions. In the periapical environment, the presence of endodontic pathogens and its products (such as LPS) triggers the host inflammatory immune response. The analysis of gene expression signatures of periapical lesions allows for the discrimination of osteolytic activity status in “active” or “inactive” according to RANKL/OPG expression ratio. Active periapical lesions are characterized by high RANKL/OPG ratio is an association with a pro-inflammatory milieu, which includes a high level of IFN-g and IL-17. Distinct patterns of IFNg and IL-17 expression were described in periapical lesions, suggesting that Th1 and Th17 subsets, described to be mutually inhibitory, can drive apical periodontitis development independently. The presence of PMNs and mast cells also have been associated with lesion activity. Conversely, inactive lesions are characterized by a low RANKL/OPG ratio is an association with an anti-inflammatory milieu, which is supposed to involve a cooperative immunoregulatory network composed by Th2 and Tregs subsets, as well by MSCs. The prototypical Th2 cytokine IL-4 is described to induce the expression of CCL22, a main chemoattractant of Tregs. Noteworthy, Tregs hallmark products, such as IL-10 and TGF-β, are described to boost MSCs immunosuppressive properties. Interestingly, a recent study points to RANKL as an unexpected immunoregulatory feedback trigger via Tregs induction.

Figure 3

Osteoimmunology at the osteosarcoma (OS) niche. Tumor-Associated Macrophages (TAMs), Tumor-Infiltrating Lymphocytes (TILs) and Mesenchymal Stem cells (MSCs) regulate osteosarcoma cells (OSCs) proliferation, tumor mass progression, and metastasis. The RANK/RANKL signaling leads to both OSCs progression and increased osteoclast activation and bone loss in the OS niche.

Figure 4

Immune response and bone crosstalk during temporomandibular joint osteoarthritis. The sustained functional overload that exceeds the joint adaptive capacity can induce dysfunctional remodeling. This dysfunctional remodeling is characterized by increased oxidative stress, due to hypoxia/reperfusion effect, and higher levels of catabolic enzymes that degrade the fibrocartilage extracellular matrix and induce chondrocyte apoptosis. The molecular products derived from cartilage breakdown (e.g., LMW-HA or PG) can trigger the immuno-inflammatory response by interacting with APCs and finally resulting in the activation of Th17 lymphocytes and the RANK/RANKL/OPG axis, leading to subchondral bone resorption. The normal joint load of the TMJ, such as static loading during swallowing or teeth clenching, induces an adaptive functional remodeling of joint tissues and promotes fibrocartilage healing. HYAL, hyaluronidase; LMW-HA, low molecular weight hyaluronan; NOS, nitric oxide; OPG, osteoprotegerin; ROS, reactive oxygen species; sRANKL; soluble receptor activator of nuclear factor-kappa B ligand; APCs, Antigen presenting cells.