Tissue Engineering Research Group (TERG), Department of Anatomy, Royal College of Surgeons in Ireland (RCSI), Dublin 2, Ireland.
Trinity Centre for Bioengineering, Trinity College Dublin (TCD), Dublin 2, Ireland.
Sci Rep. 2017 Sep 13;7(1):11494. doi: 10.1038/s41598-017-11801-0.
Craniosynostosis is a bone developmental disease where premature ossification of the cranial sutures occurs leading to fused sutures. While biomechanical forces have been implicated in craniosynostosis, evidence of the effect of microenvironmental stiffness changes in the osteogenic commitment of cells from the sutures is lacking. Our aim was to identify the differential genetic expression and osteogenic capability between cells from patent and fused sutures of children with craniosynostosis and whether these differences are driven by changes in the stiffness of the microenvironment. Cells from both sutures demonstrated enhanced mineralisation with increasing substrate stiffness showing that stiffness is a stimulus capable of triggering the accelerated osteogenic commitment of the cells from patent to fused stages. The differences in the mechanoresponse of these cells were further investigated with a PCR array showing stiffness-dependent upregulation of genes mediating growth and bone development (TSHZ2, IGF1), involved in the breakdown of extracellular matrix (MMP9), mediating the activation of inflammation (IL1β) and controlling osteogenic differentiation (WIF1, BMP6, NOX1) in cells from fused sutures. In summary, this study indicates that stiffer substrates lead to greater osteogenic commitment and accelerated bone formation, suggesting that stiffening of the extracellular environment may trigger the premature ossification of the sutures.
颅缝早闭是一种骨骼发育疾病，颅骨缝过早骨化导致缝合线融合。虽然生物力学因素与颅缝早闭有关，但缺乏缝合线细胞的微环境硬度变化对成骨细胞分化的影响的证据。我们的目的是确定颅缝早闭患儿未融合和融合颅缝细胞之间的差异基因表达和成骨能力，以及这些差异是否是由微环境硬度变化驱动的。来自未融合和融合颅缝的细胞在基质硬度增加时表现出增强的矿化，这表明硬度是一种能够触发细胞从未融合到融合阶段加速成骨的刺激因素。进一步通过 PCR 阵列研究了这些细胞的机械反应差异，结果显示与生长和骨骼发育相关的基因（TSHZ2、IGF1）、参与细胞外基质降解（MMP9）、介导炎症激活（IL1β）和控制成骨分化（WIF1、BMP6、NOX1）的基因在融合颅缝细胞中表现出依赖于硬度的上调。总之，这项研究表明，更硬的基质会导致更大的成骨能力和更快的骨形成，这表明细胞外环境的变硬可能会引发缝合线的过早骨化。
