BMAL1 Deficiency Contributes to Mandibular Dysplasia by Upregulating MMP3

Area of Science:

• Genetics
• Molecular Biology
• Craniofacial Development

Background:

• Skeletal mandibular hypoplasia (SMH) is a craniofacial deformity impacting function and potentially causing obstructive sleep apnea.
• The core circadian rhythm component, BMAL1 (brain and muscle ARNT-like 1), is crucial for biological timing.
• Reduced BMAL1 levels are observed in juvenile SMH patients' mandibles.

Purpose of the Study:

• To investigate the role of BMAL1 in the pathogenesis of skeletal mandibular hypoplasia.
• To identify molecular mechanisms linking BMAL1 deficiency to SMH.
• To explore the relationship between BMAL1 and matrix metallopeptidase 3 (MMP3) in SMH.

Main Methods:

• Analysis of BMAL1 levels in juvenile SMH patients.
• Phenotypic observation of SMH in circadian-rhythm-disrupted and BMAL1-deficient mice.
• RNA sequencing and protein chip analysis to identify BMAL1 targets.
• Investigating the transcriptional regulation of MMP3 by BMAL1.

Main Results:

• BMAL1 was significantly decreased in the mandibles of juvenile SMH patients.
• SMH was observed in mice with disrupted circadian rhythms or BMAL1 deficiency.
• Matrix metallopeptidase 3 (MMP3) was identified as a potential BMAL1 target and was increased in juvenile SMH patients.
• BMAL1 deficiency upregulated MMP3 transcription via p65 phosphorylation.

Conclusions:

• BMAL1 plays a critical role in mandibular development.
• BMAL1 deficiency contributes to SMH pathogenesis, partly through the upregulation of MMP3.
• Understanding the BMAL1-MMP3 axis offers insights into SMH mechanisms and potential therapeutic targets.