Overactive autophagy is a pathological mechanism underlying premature suture ossification in nonsyndromic craniosynostosis.
Shanshan QiuJing WangSiqi HuangShouqing SunZhen ZhangNan BaoPublished in: Scientific reports (2018)
Nonsyndromic craniosynostosis (NSC) is the most common craniosynostosis with the primary defect being one or more fused sutures. In contrast to syndromic craniosynostosis, the etiopathogenesis of NSC is largely unknown. Here we show that autophagy, a major catabolic process required for the maintenance of bone homeostasis and bone growth, is a pathological change associated with NSC. Using calvarial suture mesenchymal cells (SMCs) isolated from the fused and unfused sutures of NSC patients, we demonstrate that during SMC differentiation, the level of the autophagosomal marker LC3-II increases as osteogenic differentiation progresses, particularly at differentiation day 7, a stage concurrent with mineralization. In fused SMCs, autophagic induction was more robust than that in unfused SMCs, which consequently led to enhanced mineralized nodule formation. Perturbation of autophagy with rapamycin or wortmannin promoted or inhibited the ossification of SMCs, respectively. Our findings suggest that autophagy is essential for the osteogenic differentiation of SMCs and that overactive autophagy is a molecular abnormality underlying premature calvarial ossification in NSC.
Keyphrases
- cell death
- endoplasmic reticulum stress
- induced apoptosis
- bone regeneration
- oxidative stress
- signaling pathway
- cell cycle arrest
- end stage renal disease
- ejection fraction
- chronic kidney disease
- stem cells
- mesenchymal stem cells
- bone mineral density
- newly diagnosed
- squamous cell carcinoma
- intellectual disability
- autism spectrum disorder
- mass spectrometry
- prognostic factors
- radiation therapy
- peritoneal dialysis
- bone loss
- patient reported outcomes
- locally advanced