title: Bisphosphonate Induces Osteonecrosis of the Jaw in Diabetic Mice via NLRP3/Caspase-1-Dependent IL-1β Mechanism.
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 P2X7 R, 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.
authors.affiliation: Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA.
authors.forename: Qunzhou
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA.
authors.forename: Weihua
authors.initials: W
authors.lastname: Yu
authors.affiliation: Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA.
authors.forename: Sumin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA.
authors.forename: Qilin
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Division of Transplantation, Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Naji
authors.affiliation: Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA.|Department of Oral and Maxillofacial Surgery, Penn Medicine Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Anh D
authors.initials: AD
authors.lastname: Le
mesh_terms: D000818:Animals; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000188:drug therapy*; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism*; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004164:Diphosphonates / Q000737:chemistry / Q000627:therapeutic use*; D005786:Gene Expression Regulation; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D007150:Immunohistochemistry; D058847:Inflammasomes / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017382:Reactive Oxygen Species / Q000378:metabolism; D013696:Temperature; D014945:Wound Healing; D055114:X-Ray Microtomography; D000077211:Zoledronic Acid
chemical_list: D002352:Carrier Proteins; D004164:Diphosphonates; C508585:IL1B protein, human; C587672:IL1B protein, mouse; D007093:Imidazoles; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; D000077211:Zoledronic Acid; D020170:Caspase 1
keywords: BISPHOSPHONATE; BRONJ; DIABETES; NLRP3; OSTEONECROSIS OF THE JAW