Matrix Gla Protein Deficiency Impairs Nasal Septum Growth Causing Midface Hypoplasia [Developmental Biology]

Genetic and environmental factors may lead to abnormal growth of the orofacial skeleton affecting the overall structure of the face. In the current 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 (MGP) gene. Keutel syndrome patients show diffuse ectopic calcification of cartilaginous tissues and impaired midface development. Our comparative cephalometric analyses of micro-CT images revealed a severe midface hypoplasia in Mgp-/- mice. In vivo reporter studies demonstrated that the Mgp promoter is highly active at the cranial sutures, cranial base synchondroses and nasal septum. While sutures and cranial base synchondroses showed normal anatomical features, the nasal septum was found to be abnormally mineralized and shortened in Mgp-/- mice. Transgenic restoration of Mgp 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 upregulation of markers for hypertrophic chondrocytes, TUNEL assay showed a marked increase of apoptotic chondrocytes in the calcified nasal septum. Transmission electron microscopy confirmed unusual mineral deposits in the septal extracellular matrix (ECM) of the mutant mice. Of note, systemic reduction of inorganic phosphate level was sufficient to prevent nasal septum mineralization in Mgp-/-;Hyp compound mutants. Our work provides evidence that modulation of local and systemic factors regulating ECM mineralization can be possible therapeutic strategies to prevent ectopic cartilage calcification and some forms of congenital craniofacial anomalies in humans.

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