Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Department of Biochemistry and Molecular Biology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Stem Cell Reports. 2018 Jan 9;10(1):180-195. doi: 10.1016/j.stemcr.2017.11.017. Epub 2017 Dec 21.
Skeletal mandibular hypoplasia (SMH), one of the common types of craniofacial deformities, seriously affects appearance, chewing, pronunciation, and breathing. Moreover, SMH is prone to inducing obstructive sleep apnea syndrome. We found that brain and muscle ARNT-like 1 (BMAL1), the core component of the molecular circadian oscillator, was significantly decreased in mandibles of juvenile SMH patients. Accordingly, SMH was observed in circadian-rhythm-disrupted or BMAL1-deficient mice. RNA sequencing and protein chip analyses suggested that matrix metallopeptidase 3 (MMP3) is the potential target of BMAL1. Interestingly, in juvenile SMH patients, we observed that MMP3 was obviously increased. Consistently, MMP3 was upregulated during the whole growth period of 3-10 weeks in Bmal1 mice. Given these findings, we set out to characterize the underlying mechanism and found BMAL1 deficiency enhanced Mmp3 transcription through activating p65 phosphorylation. Together, our results provide insight into the mechanism by which BMAL1 is implicated in the pathogenesis of SMH.
下颌骨发育不全（SMH）是一种常见的颅面畸形，严重影响外观、咀嚼、发音和呼吸。此外，SMH 容易诱发阻塞性睡眠呼吸暂停综合征。我们发现，脑和肌肉 ARNT 样蛋白 1（BMAL1），分子昼夜节律振荡器的核心组成部分，在下颌骨发育不全的青少年患者中明显减少。因此，在昼夜节律紊乱或 BMAL1 缺陷的小鼠中观察到了 SMH。RNA 测序和蛋白质芯片分析表明，基质金属蛋白酶 3（MMP3）是 BMAL1 的潜在靶标。有趣的是，在青少年 SMH 患者中，我们观察到 MMP3 明显增加。一致的是，在 Bmal1 小鼠的整个生长过程（3-10 周）中，MMP3 均上调。鉴于这些发现，我们着手研究其潜在机制，并发现 BMAL1 缺乏通过激活 p65 磷酸化增强 Mmp3 转录。总的来说，我们的研究结果为 BMAL1 参与 SMH 发病机制的机制提供了深入的了解。
