Marulanda Juliana, Eimar Hazem, McKee Marc D, Berkvens Michelle, Nelea Valentin, Roman Hassem, Borrás Teresa, Tamimi Faleh, Ferron Mathieu, Murshed Monzur
From the Faculty of Dentistry, McGill University, Montreal, Quebec H3A 1G1, Canada.
the Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Montreal, Quebec H3A 0C7, Canada.
J Biol Chem. 2017 Jul 7;292(27):11400-11412. doi: 10.1074/jbc.M116.769802. Epub 2017 May 9.
Genetic and environmental factors may lead to abnormal growth of the orofacial skeleton, affecting the overall structure of the face. In this study, we investigated the craniofacial abnormalities in a mouse model for Keutel syndrome, a rare genetic disease caused by loss-of-function mutations in the matrix Gla protein () gene. Keutel syndrome patients show diffuse ectopic calcification of cartilaginous tissues and impaired midface development. Our comparative cephalometric analyses of micro-computed tomography images revealed a severe midface hypoplasia in mice. reporter studies demonstrated that the promoter is highly active at the cranial sutures, cranial base synchondroses, and nasal septum. Interestingly, the cranial sutures of the mutant mice showed normal anatomical features. Although we observed a mild increase in mineralization of the spheno-occipital synchondrosis, it did not reduce the relative length of the cranial base in comparison with total skull length. Contrary to this, we found the nasal septum to be abnormally mineralized and shortened in mice. Transgenic restoration of expression in chondrocytes fully corrected the craniofacial anomalies caused by MGP deficiency, suggesting a local role for MGP in the developing nasal septum. Although there was no up-regulation of markers for hypertrophic chondrocytes, a TUNEL assay showed a marked increase in apoptotic chondrocytes in the calcified nasal septum. Transmission electron microscopy confirmed unusual mineral deposits in the septal extracellular matrix of the mutant mice. Of note, the systemic reduction of the inorganic phosphate level was sufficient to prevent abnormal mineralization of the nasal septum in compound mutants. Our work provides evidence that modulation of local and systemic factors regulating extracellular matrix mineralization can be possible therapeutic strategies to prevent ectopic cartilage calcification and some forms of congenital craniofacial anomalies in humans.
遗传和环境因素可能导致口面部骨骼异常生长，影响面部整体结构。在本研究中，我们调查了Keutel综合征小鼠模型中的颅面异常情况，Keutel综合征是一种由基质Gla蛋白（MGP）基因功能丧失突变引起的罕见遗传病。Keutel综合征患者表现出软骨组织的弥漫性异位钙化和中面部发育受损。我们对微型计算机断层扫描图像进行的比较头影测量分析显示，Mgp-/-小鼠存在严重的中面部发育不全。报告基因研究表明，MGP启动子在颅缝、颅底软骨结合和鼻中隔处高度活跃。有趣的是，突变小鼠的颅缝显示出正常的解剖特征。虽然我们观察到蝶枕软骨结合处的矿化略有增加，但与全颅骨长度相比，它并没有缩短颅底的相对长度。与此相反，我们发现Mgp-/-小鼠的鼻中隔异常矿化且缩短。软骨细胞中MGP表达的转基因恢复完全纠正了由MGP缺乏引起的颅面异常，表明MGP在发育中的鼻中隔中起局部作用。虽然肥大软骨细胞标记物没有上调，但TUNEL检测显示钙化鼻中隔中的凋亡软骨细胞显著增加。透射电子显微镜证实突变小鼠鼻中隔细胞外基质中存在异常矿物质沉积。值得注意的是，无机磷酸盐水平的全身降低足以防止Mgp-/-复合突变体中鼻中隔的异常矿化。我们的工作提供了证据，表明调节调节细胞外基质矿化的局部和全身因素可能是预防人类异位软骨钙化和某些形式先天性颅面异常的治疗策略。
