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Stem Cell Reports. 2018 Jan 9;10(1):180-195. doi: 10.1016/j.stemcr.2017.11.017. Epub 2017 Dec 21.

BMAL1 Deficiency Contributes to Mandibular Dysplasia by Upregulating MMP3.

Author information

1
Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
2
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.
3
Center for Craniofacial Regeneration, College of Dental Medicine, Columbia University Medical Center, New York, NY 10032, USA.
4
Department of Otolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
5
Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: lily-c1030@163.com.

Abstract

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.

KEYWORDS:

BMAL1; circadian clock gene; circadian rhythm; metallopeptidase 3; p65; skeletal mandibular hypoplasia

PMID:
29276151
PMCID:
PMC5768965
DOI:
10.1016/j.stemcr.2017.11.017
[Indexed for MEDLINE]
Free PMC Article

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