Departmental Papers (Dental)

Document Type

Journal Article

Date of this Version

12-1-2015

Publication Source

Journal of Bone and Mineral Research

Volume

30

Issue

12

Start Page

2300

Last Page

2312

DOI

10.1002/jbmr.2577

Abstract

Diabetes mellitus is an established risk factor associated with bisphosphonate-related osteonecrosis of the jaw (BRONJ). Sustained activation of Nod-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome contributes to the persistent inflammation and impaired cutaneous wound healing in diabetic mice and human. We have recently demonstrated a compelling linkage between M1 macrophages and BRONJ conditions in both murine and human diseases. The aim of this study was to determine whether NLRP3 inflammasome activation is involved in BRONJ development in diabetic mice. We showed an increased incidence of delayed oral wound healing and bone necrosis of extraction sockets in db/db mice compared with those in nondiabetic db/+ controls, which correlated with an elevated expression of NLRP3, caspase-1, and IL-1β in macrophages residing at local wounds. Constitutively, bone marrow-derived macrophages from db/db mice (db/db BMDMs) secrete a relatively higher level of IL-1β than those from db/+ mice (db/+ BMDMs). Upon stimulation by NLRP3 activators, the secretion of IL-1β by db/db BMDMs was 1.77-fold higher than that by db/+ BMDMs (p < 0.001). Systemic treatment of mice with zoledronate (Zol), a nitrogen-containing bisphosphonate, resulted in a 1.86- and 1.63-fold increase in NLRP3/caspase-1-dependent IL-1β secretion by db/+ and db/db BMDMs, respectively, compared with BMDMs derived from nontreated mice (p < 0.001). Importantly, systemic administration of pharmacological inhibitors of NLRP3 activation improved oral wound healing and suppressed BRONJ formation in db/db mice. Mechanistically, we showed that supplementation with intermediate metabolites of the mevalonate pathway, inhibitors of caspase-1 and NLRP3 activation, an antagonist for P2X7R, or a scavenger of reactive oxygen species (ROS), robustly abolished Zol-enhanced IL-1β release from macrophages in response to NLRP3 activation (p < 0.001). Our findings suggest that diabetes-associated chronic inflammatory response may have contributed to impaired socket wound healing and rendered oral wound susceptible to the development of BRONJ via NLRP3 activation in macrophages. © 2015 American Society for Bone and Mineral Research.

Keywords

BISPHOSPHONATE, BRONJ, DIABETES, NLRP3, OSTEONECROSIS OF THE JAW, Animals, Bisphosphonate-Associated Osteonecrosis of the Jaw, Carrier Proteins, Caspase 1, Cell Line, Diabetes Mellitus, Experimental, Diphosphonates, Gene Expression Regulation, Humans, Imidazoles, Immunohistochemistry, Inflammasomes, Interleukin-1beta, Macrophages, Male, Mice, NLR Family, Pyrin Domain-Containing 3 Protein, Reactive Oxygen Species, Temperature, Wound Healing, X-Ray Microtomography, cryopyrin, glibenclamide, glucose, interleukin 17, interleukin 1beta, interleukin 1beta converting enzyme, mevalonic acid, reactive oxygen metabolite, zoledronic acid, bisphosphonic acid derivative, carrier protein, cryopyrin, IL1B protein, human, IL1B protein, mouse, imidazole derivative, inflammasome, interleukin 1beta, interleukin 1beta converting enzyme, Nlrp3 protein, mouse, zoledronic acid, animal cell, animal experiment, animal model, Article, bone defect, bone marrow derived macrophage, controlled study, cytokine release, disease course, enzyme activation, fracture healing, human, human cell, jaw osteonecrosis, macrophage, male, mouse, non insulin dependent diabetes mellitus, nonhuman, protein expression, systemic therapy, wound healing impairment, animal, Bisphosphonate-Associated Osteonecrosis of the Jaw, cell line, chemistry, experimental diabetes mellitus, gene expression regulation, immunohistochemistry, metabolism, micro-computed tomography, temperature, wound healing

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Date Posted: 09 February 2023

This document has been peer reviewed.