Tlr2/4-Mediated Hyperinflammation Promotes Cherubism-Like Jawbone Expansion in Sh3bp2 (P416R) Knockin Mice.
Tlr2/4-Mediated Hyperinflammation Promotes Cherubism-Like Jawbone Expansion in Sh3bp2 (P416R) Knockin Mice.
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作者：
Fujii Y;Monteiro N;Sah SK;Javaheri H;Ueki Y;Fan Z;Reichenberger EJ;Chen IP
Cherubism (CBM) 的特征是颌骨扩张并伴有多房性纤维囊性病变，是由 SH3 结构域结合蛋白 2（SH3BP2；小鼠直系同源物 Sh3bp2）的功能获得性突变引起的。颌骨和牙齿完整性的丧失会显着降低受影响儿童的生活质量。 CBM 的治疗仅限于通过多次手术来矫正面部畸形。尽管 CBM 敲入 (KI) 小鼠模型 (Sh3bp2 KI/KI) 取得了重大进展，但 CBM 损伤的激活机制仍然未知，因为突变小鼠不会自发发育出可扩展的颌骨。我们假设不明原因的骨炎症会引发 CBM 中的颌骨扩张。为了以时空控制的方式引入颌骨炎症，我们暴露了 6 周龄 Sh3bp2 +/+ 、Sh3bp2 KI/+ 和 Sh3bp2 KI/KI 小鼠的右下颌第一磨牙的牙髓。细菌从暴露的牙髓侵入根管，导致野生型和突变型小鼠出现根尖周炎。病原体相关分子模式 (PAMP) 诱导的牙槽骨炎症导致 Sh3bp2 KI/+ 和 Sh3bp2 KI/KI 小鼠颌骨扩张。 CBM 样病变随着中性粒细胞、巨噬细胞和破骨细胞数量的增加而加剧炎症。与 Sh3bp2 +/+ 小鼠相比，这些病变显示出过多的中性粒细胞胞外陷阱 (NET)。在 Sh3bp2 +/+ 、Sh3bp2 KI/+ 和 Sh3bp2 KI/KI 小鼠的根尖周病变中，以及在 Sh3bp2 KI/KI 小鼠的血浆和左侧未处理的下颌骨（没有牙髓暴露）中，IL-1β、IL-6 和 TNF-α 的表达水平升高，表明全身性上调。 Ly6G 抗体消除 Tlr2/4 信号传导或消除中性粒细胞可改善 Sh3bp2 KI/KI 小鼠中 PAMP 诱导的颌骨扩张。总之，在 CBM 小鼠的颌部成功诱导 CBM 样病变对于研究 CBM 的启动机制和测试潜在的疗法非常重要。我们的研究结果进一步强调了宿主免疫在根尖牙周炎发展中的关键作用以及维持 CBM 患者口腔健康的重要性。 © 2021 作者。 JBMR Plus 由 Wiley periodicals LLC 代表美国骨与矿物研究学会出版。
Cherubism (CBM), characterized by expansile jawbones with multilocular fibrocystic lesions, is caused by gain‐of‐function mutations in SH3 domain‐binding protein 2 (SH3BP2; mouse orthologue Sh3bp2). Loss of jawbone and dental integrity significantly decrease the quality of life for affected children. Treatment for CBM is limited to multiple surgeries to correct facial deformities. Despite significant advances made with CBM knockin (KI) mouse models (Sh3bp2 KI/KI ), the activation mechanisms of CBM lesions remain unknown because mutant mice do not spontaneously develop expansile jawbones. We hypothesize that bony inflammation of an unknown cause triggers jawbone expansion in CBM. To introduce jawbone inflammation in a spatiotemporally controlled manner, we exposed pulp of the first right mandibular molar of 6‐week‐old Sh3bp2 +/+ , Sh3bp2 KI/+ , and Sh3bp2 KI/KI mice. Bacterial invasion from the exposed pulp into root canals led to apical periodontitis in wild‐type and mutant mice. The pathogen‐associated molecular patterns (PAMPs)‐induced inflammation of alveolar bone resulted in jawbone expansion in Sh3bp2 KI/+ and Sh3bp2 KI/KI mice. CBM‐like lesions developed exacerbated inflammation with increased neutrophil, macrophage, and osteoclast numbers. These lesions displayed excessive neutrophil extracellular traps (NETs) compared to Sh3bp2 +/+ mice. Expression levels of IL‐1β, IL‐6, and TNF‐α were increased in periapical lesions of Sh3bp2 +/+ , Sh3bp2 KI/+ , and Sh3bp2 KI/KI mice and also in plasma and the left untreated mandibles (with no pulp exposure) of Sh3bp2 KI/KI mice, suggesting a systemic upregulation. Ablation of Tlr2/4 signaling or depletion of neutrophils by Ly6G antibodies ameliorated jawbone expansion induced by PAMPs in Sh3bp2 KI/KI mice. In summary, successful induction of CBM‐like lesions in jaws of CBM mice is important for studying initiating mechanisms of CBM and for testing potential therapies. Our findings further emphasize a critical role of host immunity in the development of apical periodontitis and the importance of maintaining oral health in CBM patients. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.