Abstract
Bone remodeling is tightly controlled by osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Fine tuning of the osteoclast–osteoblast balance results in strict synchronization of bone resorption and formation, which maintains structural integrity and bone tissue homeostasis; in contrast, dysregulated bone remodeling may cause pathological osteolysis, in which inflammation plays a vital role in promoting bone destruction. The alveolar bone presents high turnover rate, complex associations with the tooth and periodontium, and susceptibility to oral pathogenic insults and mechanical stress, which enhance its complexity in host defense and bone remodeling. Alveolar bone loss is also involved in systemic bone destruction and is affected by medication or systemic pathological factors. Therefore, it is essential to investigate the osteoimmunological mechanisms involved in the dysregulation of alveolar bone remodeling. The inflammasome is a supramolecular protein complex assembled in response to pattern recognition receptors and damage-associated molecular patterns, leading to the maturation and secretion of pro-inflammatory cytokines and activation of inflammatory responses. Pyroptosis downstream of inflammasome activation also facilitates the clearance of intracellular pathogens and irritants. However, inadequate or excessive activity of the inflammasome may allow for persistent infection and infection spreading or uncontrolled destruction of the alveolar bone, as commonly observed in periodontitis, periapical periodontitis, peri-implantitis, orthodontic tooth movement, medication-related osteonecrosis of the jaw, nonsterile or sterile osteomyelitis of the jaw, and osteoporosis. In this review, we present a framework for understanding the role and mechanism of canonical and noncanonical inflammasomes in the pathogenesis and development of etiologically diverse diseases associated with alveolar bone loss. Inappropriate inflammasome activation may drive alveolar osteolysis by regulating cellular players, including osteoclasts, osteoblasts, osteocytes, periodontal ligament cells, macrophages, monocytes, neutrophils, and adaptive immune cells, such as T helper 17 cells, causing increased osteoclast activity, decreased osteoblast activity, and enhanced periodontium inflammation by creating a pro-inflammatory milieu in a context- and cell type-dependent manner. We also discuss promising therapeutic strategies targeting inappropriate inflammasome activity in the treatment of alveolar bone loss. Novel strategies for inhibiting inflammasome signaling may facilitate the development of versatile drugs that carefully balance the beneficial contributions of inflammasomes to host defense.
Highlights
The alveolar bone, an important part of the maxillofacial skeleton, is a connective tissue that supports teeth, is subjected to mechanical stress, and undergoes continuous bone remodeling [1]
Similar evidence shows that Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) expression is increased in RAW 264 cells infected with A. actinomycetemcomitans, it may not be the most vital player in promoting inflammatory bone loss in this scenario: inhibition of reactive oxygen species (ROS) and cathepsin B rather than Nlrp3 knockdown can prevent increased IL-1b secretion, and the bone resorption activity of osteoclasts differentiated from Nlrp3-deficient macrophages of mice with experimental periodontitis induced by A. actinomycetemcomitans is even increased [250, 251]
Nlrc4-knockout mice exhibit greater bone resorption than wild-type mice, and osteoclast activity is increased in Nlrc4-deficient macrophages, suggesting a protective role of Nucleotide-binding oligomerization domain-like receptors (NLRs) family CARD domain-containing protein 4 (NLRC4) inflammasomes in inflammatory bone resorption in periodontitis induced by A. actinomycetemcomitans, which may be attributed to NLRP3 inflammasome activation [254]
Summary
The alveolar bone, an important part of the maxillofacial skeleton, is a connective tissue that supports teeth, is subjected to mechanical stress, and undergoes continuous bone remodeling [1]. We focus on the roles of inflammasomes in the pathogenesis and development of diseases related to dysregulated alveolar bone remodeling, provide an update of current knowledge of the possible effects of inflammasome activity on different cell types (including but not limited to osteoclasts, osteoblasts, macrophages, monocytes, and periodontal ligament cells) in etiologically diverse diseases, and summarize current research gaps and potential developments in the field (Table 2).
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