Department of Biomedical Genetics, Center for Oral Biology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Sci Signal. 2010 May 25;3(123):ra40. doi: 10.1126/scisignal.2000727.
Craniosynostosis, a developmental disorder resulting from premature closure of the gaps (sutures) between skull bones, can be caused by excessive intramembranous ossification, a type of bone formation that does not involve formation of a cartilage template (chondrogenesis). Here, we show that endochondral ossification, a type of bone formation that proceeds through a cartilage intermediate, caused by switching the fate of mesenchymal stem cells to chondrocytes, can also result in craniosynostosis. Simultaneous knockout of Axin2, a negative regulator of the WNT-beta-catenin pathway, and decreased activity of fibroblast growth factor (FGF) receptor 1 (FGFR1) in mice induced ectopic chondrogenesis, leading to abnormal suture morphogenesis and fusion. Genetic analyses revealed that activation of beta-catenin cooperated with FGFR1 to alter the lineage commitment of mesenchymal stem cells to differentiate into chondrocytes, from which cartilage is formed. We showed that the WNT-beta-catenin pathway directly controlled the stem cell population by regulating its renewal and proliferation, and indirectly modulated lineage specification by setting the balance of the FGF and bone morphogenetic protein pathways. This study identifies endochondral ossification as a mechanism of suture closure during development and implicates this process in craniosynostosis.
颅缝早闭是一种由于颅骨骨缝过早闭合而导致的发育障碍，其原因可能是骨膜内过度成骨，这是一种不涉及软骨模板形成（软骨发生）的成骨类型。在这里，我们表明，通过将间充质干细胞的命运转变为软骨细胞，引发的软骨内骨化（一种通过软骨中间产物进行的成骨类型）也会导致颅缝早闭。在小鼠中同时敲除 WNT-β-连环蛋白通路的负调节剂 Axin2 和下调成纤维细胞生长因子（FGF）受体 1（FGFR1）的活性，会诱导异位软骨生成，导致异常的缝融合和形态发生。遗传分析表明，β-连环蛋白的激活与 FGFR1 合作，改变了间充质干细胞的谱系决定，使其分化为软骨细胞，从而形成软骨。我们表明，WNT-β-连环蛋白通路通过调节其更新和增殖直接控制干细胞群体，并通过设定 FGF 和骨形态发生蛋白途径的平衡来间接调节谱系特化。这项研究确定了软骨内骨化是发育过程中缝闭合的一种机制，并暗示该过程与颅缝早闭有关。
