Bisphosphonate Induces Osteonecrosis of the Jaw in Diabetic Mice via NLRP3/Caspase-1-Dependent IL-1β Mechanism.
Bisphosphonate Induces Osteonecrosis of the Jaw in Diabetic Mice via NLRP3/Caspase-1-Dependent IL-1β Mechanism.
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DOI：
10.1002/jbmr.2577
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发表时间：
2015-12
期刊：
影响因子：
--
通讯作者：
Le AD
中科院分区：
文献类型：
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作者：
Zhang Q;Yu W;Lee S;Xu Q;Naji A;Le AD
糖尿病是与双膦酸盐相关性颌骨骨坏死（BRONJ）相关的一个确定的危险因素。nod样受体（NLR）家族、pyrin结构域蛋白3 （NLRP3）炎性小体的持续激活有助于糖尿病小鼠和人的持续炎症和皮肤伤口愈合受损。我们最近证明了小鼠和人类疾病中M1巨噬细胞和BRONJ状况之间的令人信服的联系。本研究的目的是确定NLRP3炎性体激活是否参与糖尿病小鼠BRONJ的发展。我们发现，与非糖尿病db/+对照组相比，db/db小鼠口腔伤口延迟愈合和拔牙窝骨坏死的发生率增加，这与局部伤口巨噬细胞中NLRP3、caspase-1和IL-1β的表达升高有关。构成性地，来自db/db小鼠（db/db BMDMs）的骨髓源性巨噬细胞分泌的IL-1β水平相对高于来自db/+小鼠（db/+ BMDMs）。在NLRP3激活剂刺激下，db/db BMDMs分泌的IL-1β比db/+ BMDMs高1.77倍（p<0.001）。用含氮双膦酸盐唑来膦酸钠（Zol）全身治疗小鼠，与未治疗小鼠的BMDMs相比，db/+和db/db BMDMs分泌NLRP3/caspase-1依赖性IL-1β分别增加1.86倍和1.63倍（p<0.001）。重要的是，在db/db小鼠中，全身给药NLRP3激活的药理学抑制剂可改善口腔伤口愈合并抑制BRONJ的形成。在机制上，我们发现补充甲羟丙酸途径的中间代谢物、caspase-1和NLRP3激活抑制剂、P2X7R拮抗剂或活性氧（ROS）清除剂，可以有效地消除zol增强的巨噬细胞对NLRP3激活的IL-1β释放（p<0.001）。我们的研究结果表明，糖尿病相关的慢性炎症反应可能导致窝口伤口愈合受损，并通过巨噬细胞中NLRP3的激活使口腔伤口易受BRONJ的影响。这篇文章受版权保护。版权所有
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 as compared to those in non-diabetic 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, in comparison to BMDMs derived from non-treated 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. This article is protected by copyright. All rights reserved