BMAL1 Deficiency Contributes to Mandibular Dysplasia by Upregulating MMP3

Abstract

SummarySkeletal 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.

Circadian BMAL1 regulates mandibular condyle development by hedgehog pathway

“…Takarada et al also found the body length measured from nose to anus and the longitudinal lengths of both tibia and femur decreased remarkably in BMAL1‐deficient mice than wild‐type mice . Our previous study also demonstrated that osteogenic differentiation is reduced in limb and mandible from Bmal1 ‐/‐ mice . Unlike the limb bone and maxillary and mandibular body which mainly rely on intramembranous osteogenesis, MCC is considered as a secondary cartilage and has significant structural differences from primary cartilages .…”

BMAL1 deficiency promotes skeletal mandibular hypoplasia via OPG downregulation

“…Additionally, OPG‐deficient male mice can serve as a model for studying severe alveolar bone loss . We previously deployed a protein chip analysis and found that OPG expression in the mandible was decreased significantly in Bmal1 −/ − mice compared with wild‐type mice …”

Bmal1 Regulates Coagulation Factor Biosynthesis in Mouse Liver in Streptococcus oralis Infection

“…All mice were maintained under 12/12-h light/dark cycles with the light on from 8:00 a.m. (Zeitgeber time 0, ZT0) to 8:00 p.m. (ZT12) and fed antibiotic-free food and water ad libitum . In the experiment, C57BL/6J mice were placed on a previously described jet-lagged schedule with 8-h light advanced every 2–3 days for 12 weeks, which mimicked the circadian disturbance that humans undergo during shift work (Zhao et al, 2017 ). PT was mildly shortened, while APTT was significantly prolonged, and the fibrinogen reaction time was shortened owing to elevated plasma fibrinogen in jet-lagged mice ( Figure 5A ).…”