Microbe-Dependent Exacerbated Alveolar Bone Destruction in Heterozygous Cherubism Mice.
Microbe-Dependent Exacerbated Alveolar Bone Destruction in Heterozygous Cherubism Mice.
复制标题
杂合子天使小鼠中微生物依赖性加剧的牙槽骨破坏。
DOI：
10.1002/jbm4.10352
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发表时间：
2020
期刊：
影响因子：
3.8
通讯作者：
Ueki,Yasuyoshi
中科院分区：
文献类型：
--
作者：
Kittaka,Mizuho;Yoshimoto,Tetsuya;Schlosser,Collin;Kajiya,Mikihito;Kurihara,Hidemi;Reichenberger,ErnstJ;Ueki,Yasuyoshi
Cherubism (OMIM#118400) 是一种颅面疾病，其特征是破坏性下颌扩张。 SH3 结构域结合蛋白 2 (SH3BP2) 的功能突变是造成这种罕见疾病的原因。我们之前已经证明，纯合敲入 (KI) 小鼠 (Sh3bp2KI/KI) 通过在颌骨中产生炎症病变来重现人类的天性。然而，尽管所有突变在人类中都是杂合的，但为什么杂合 KI 小鼠 (Sh3bp2KI/+) 不能重现人类天使般的过度颌骨破坏，目前仍不清楚。我们假设 Sh3bp2KI/+ 小鼠需要接受挑战以发展加剧的颌骨破坏，并且口腔中的细菌刺激可能与该机制有关。在这项研究中，我们将结扎诱导的牙周炎模型应用于Sh3bp2KI/+小鼠，以诱导炎症性牙槽骨破坏。结扎线放置诱导牙槽骨吸收并伴有牙龈炎症。牙槽骨体积定量显示，与Sh3bp2+/+小鼠（雄性：25.8%±4.0%，雌性：30.9%±6.5%）相比，Sh3bp2KI/+小鼠出现更严重的骨丢失（雄性：43.0%±10.6%，雌性：42.6%±10.4%）。通过水泥牙釉质连接处-牙槽骨嵴距离测量的骨损失显示Sh3bp2KI/+和Sh3bp2+/+小鼠之间没有差异。与Sh3bp2+/+小鼠相比，雄性Sh3bp2KI/+小鼠牙槽骨表面的破骨细胞数量较高，但雌性小鼠则不然。相比之下，结扎Sh3bp2KI/+和Sh3bp2+/+小鼠牙龈中的炎症细胞因子水平相当。骨髓细胞中脾酪氨酸激酶的基因缺失和抗生素治疗抑制了Sh3bp2KI/+小鼠的牙槽骨丢失，这表明SYK介导的破骨细胞分化和功能增加以及口腔细菌的积累是结扎诱导牙周炎的Sh3bp2KI/+小鼠牙槽骨丢失增加的原因。口腔卫生不足导致的大量口腔细菌负荷可能会引发人类天使颌骨破坏。 © 2020 The Authors.JBMR Plus 由 Wiley periodicals, Inc. 代表美国骨与矿物研究学会出版。
Cherubism (OMIM#118400) is a craniofacial disorder characterized by destructive jaw expansion. Gain of function mutations in SH3 domain binding protein 2 (SH3BP2) are responsible for this rare disorder. We have previously shown that homozygous knock in (KI) mice (Sh3bp2KI/KI) recapitulate human cherubism by developing inflammatory lesions in the jaw. However, it remains unknown why heterozygous KI mice (Sh3bp2KI/+) do not recapitulate the excessive jawbone destruction in human cherubism, even though all mutations are heterozygous in humans. We hypothesized thatSh3bp2KI/+mice need to be challenged for developing exacerbated jawbone destruction and that bacterial stimulation in the oral cavity may be involved in the mechanism. In this study, we applied a ligature induced periodontitis model toSh3bp2KI/+mice to induce inflammatory alveolar bone destruction. Ligature placement induced alveolar bone resorption with gingival inflammation. Quantification of alveolar bone volume revealed thatSh3bp2KI/+mice developed more severe bone loss (male: 43.0% ± 10.6%, female: 42.6% ± 10.4%) compared withSh3bp2+/+mice (male: 25.8% ± 4.0%, female: 30.9% ± 6.5%). Measurement of bone loss by the cement enamel junction–alveolar bone crest distance showed no difference betweenSh3bp2KI/+andSh3bp2+/+mice. The number of osteoclasts on the alveolar bone surface was higher in maleSh3bp2KI/+mice, but not in females, compared withSh3bp2+/+mice. In contrast, inflammatory cytokine levels in gingiva were comparable betweenSh3bp2KI/+andSh3bp2+/+mice with ligatures. Genetic deletion of the spleen tyrosine kinase in myeloid cells and antibiotic treatment suppressed alveolar bone loss inSh3bp2KI/+mice, suggesting that increased osteoclast differentiation and function mediated by SYK and accumulation of oral bacteria are responsible for the increased alveolar bone loss inSh3bp2KI/+mice with ligature induced periodontitis. High amounts of oral bacterial load caused by insufficient oral hygiene could be a trigger for the initiation of jawbone destruction in human cherubism. © 2020 The Authors.JBMR Pluspublished by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.