Bisphosphonate Induces Osteonecrosis of the Jaw in Diabetic Mice via NLRP3/Caspase-1-Dependent IL-1β Mechanism

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Departmental Papers (Dental)
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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
Dentistry
Oral and Maxillofacial Surgery
Oral Biology and Oral Pathology
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Zhang, Qunzhou
Yu, Weihua
Lee, Sumin
Xu, Qilin
Naji, Ali
Le, Anh D
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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.

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2015-12-01
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Journal of Bone and Mineral Research
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