Ueharu Hiroki, Pan Haichun, Liu Xia, Ishii Mamoru, Pongetti Jessica, Kulkarni Anshul K, Adegbenro Folasade E, Wurn Jaden, Maxson Robert E, Sun Hongchen, Komatsu Yoshihiro, Zhang Honghao, Yang Jingwen, Mishina Yuji
Department of Biologic and Materials Sciences & Prosthodontics University Michigan School of Dentistry Ann Arbor Michigan USA.
Department of Oral Pathology Hospital of Stomatology, Jilin University Changchun China.
JBMR Plus. 2023 Feb 23;7(4):e10716. doi: 10.1002/jbm4.10716. eCollection 2023 Apr.
Craniosynostosis is a congenital anomaly characterized by the premature fusion of cranial sutures. Sutures are a critical connective tissue that regulates bone growth; their aberrant fusion results in abnormal shapes of the head and face. The molecular and cellular mechanisms have been investigated for a long time, but knowledge gaps remain between genetic mutations and mechanisms of pathogenesis for craniosynostosis. We previously demonstrated that the augmentation of bone morphogenetic protein (BMP) signaling through constitutively active BMP type 1A receptor (caBmpr1a) in neural crest cells (NCCs) caused the development of premature fusion of the anterior frontal suture, leading to craniosynostosis in mice. In this study, we demonstrated that ectopic cartilage forms in sutures prior to premature fusion in mice. The ectopic cartilage is subsequently replaced by bone nodules leading to premature fusion with similar but unique fusion patterns between two neural crest-specific transgenic Cre mouse lines, and mice, which coincides with patterns of premature fusion in each line. Histologic and molecular analyses suggest that endochondral ossification in the affected sutures. Both in vitro and in vivo observations suggest a greater chondrogenic capacity and reduced osteogenic capability of neural crest progenitor cells in mutant lines. These results suggest that the augmentation of BMP signaling alters the cell fate of cranial NCCs toward a chondrogenic lineage to prompt endochondral ossification to prematurely fuse cranial sutures. By comparing and mice at the stage of neural crest formation, we found more cell death of cranial NCCs in than mice at the developing facial primordia. These findings may provide a platform for understanding why mutations of broadly expressed genes result in the premature fusion of limited sutures. © 2022 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
颅缝早闭是一种先天性异常，其特征为颅骨缝过早融合。颅骨缝是调节骨骼生长的关键结缔组织；其异常融合会导致头面部形状异常。分子和细胞机制已被研究很长时间，但颅缝早闭的基因突变与发病机制之间仍存在知识空白。我们之前证明，通过在神经嵴细胞（NCCs）中组成型激活骨形态发生蛋白（BMP）1A型受体（caBmpr1a）来增强BMP信号传导，会导致前额缝过早融合，从而在小鼠中引发颅缝早闭。在本研究中，我们证明在小鼠过早融合之前，缝线中会形成异位软骨。随后，异位软骨被骨结节取代，导致在两种神经嵴特异性转基因Cre小鼠品系（ 和 小鼠）之间出现类似但独特的融合模式的过早融合，这与每个品系中的过早融合模式一致。组织学和分子分析表明，受影响的缝线中存在软骨内成骨。体外和体内观察均表明，突变品系中的神经嵴祖细胞具有更大的软骨形成能力和更低的成骨能力。这些结果表明，BMP信号传导的增强会改变颅NCCs的细胞命运，使其向软骨形成谱系发展，从而促使软骨内成骨过早融合颅骨缝。通过比较神经嵴形成阶段的 和 小鼠，我们发现在发育中的面部原基处， 小鼠的颅NCCs细胞死亡比 小鼠更多。这些发现可能为理解为什么广泛表达的基因的突变会导致有限的缝线过早融合提供一个平台。© 2022作者。由Wiley Periodicals LLC代表美国骨与矿物质研究学会出版。
