Ogle Roy C, Tholpady Sunil S, McGlynn Kathryn A, Ogle Rebecca A
Departments of Neurological Surgery, Cell Biology and Plastic Surgery, University of Virginia, Charlottesville, Va., USA.
Cells Tissues Organs. 2004;176(1-3):54-66. doi: 10.1159/000075027.
The cranial sutures are the primary sites of bone formation during skull growth. Morphogenesis and phenotypic maintenance of the cranial sutures are regulated by tissue interactions, especially those with the underlying dura mater. Removal of the dura mater in fetuses causes abnormal suture development and premature suture obliteration. The dura mater interacts with overlying tissues of the cranial vault by providing: (1) intercellular signals, (2) mechanical signals and (3) cells, which undergo transformation and migrate to the suture. The intercellular signaling governing suture development employs the fibroblast growth factors (FGFs). In rats during formation of the sutures in the fetus, FGF-1 is localized mainly in the dura mater, while other FGFs are expressed in the overlying tissues. By birth, FGF-2 largely replaces FGF-1 in the dura mater. FGFs present in the calvaria bind either the IIIb or IIIc mRNA splice variants of the FGF receptors (FGFRs) 1, 2, or 3. Monoclonal antibodies to the b variant of FGFR2 were used to determine the distribution of FGFR2IIIb during suture development and its extracellular localization. FGFR2IIIb is present in association with mature osteoblasts and osteogenic precursor cells of the suture in the fetus. Ectodomains of FGFR2IIIb, the products of proteolytic cleavage of the receptors, were present throughout the extracellular matrix of sutures resisting obliteration (coronal and sagittal), but absent from the core of sutures undergoing normal fusion (posterior intrafrontal). This observation is consistent with a possible mechanism, in which truncated receptors bind FGFs, thus regulating free FGF available to nearby cells. Mechanical signaling in the calvaria results from tensional forces in the dura mater generated during rapid expansion of the neurocranium. Posterior intrafrontal sutures of rats, which fuse between days 16 and 24, were subjected to cyclical tensional forces in vitro. Significant delay in the timing of suture fusion and increases in the expression domains of FGFR1 and 2 were observed, demonstrating the sensitivity of suture patency to mechanical signals and a possible role of the FGF system in mediating such stimuli. Finally, cells of the dura mater beneath the intrafrontal and sagittal sutures were observed to undergo a morphological transformation to a dendritic morphology and migrate into the suture mesenchyme between days 10 and 16 of development. This process may participate in suture and bone morphogenesis and influence the patency of the sutures along the anterior-posterior axis.
颅缝是颅骨生长过程中骨形成的主要部位。颅缝的形态发生和表型维持受组织相互作用调节，尤其是与下方硬脑膜的相互作用。去除胎儿的硬脑膜会导致颅缝发育异常和过早闭合。硬脑膜通过提供以下物质与颅顶的上方组织相互作用：（1）细胞间信号，（2）机械信号，以及（3）经历转化并迁移至颅缝的细胞。调控颅缝发育的细胞间信号传导利用成纤维细胞生长因子（FGFs）。在大鼠胎儿颅缝形成过程中，FGF-1主要定位于硬脑膜，而其他FGFs则在上方组织中表达。出生时，FGF-2在很大程度上取代了硬脑膜中的FGF-1。颅骨中存在的FGFs与FGF受体（FGFRs）1、2或3的IIIb或IIIc mRNA剪接变体结合。使用针对FGFR2 b变体的单克隆抗体来确定FGFR2IIIb在颅缝发育过程中的分布及其细胞外定位。FGFR2IIIb与胎儿颅缝中的成熟成骨细胞和成骨前体细胞相关联。FGFR2IIIb的胞外域，即受体蛋白水解切割的产物，存在于抵抗闭合的颅缝（冠状缝和矢状缝）的整个细胞外基质中，但在经历正常融合的颅缝（额骨后缝）核心中不存在。这一观察结果与一种可能的机制一致，即截短的受体结合FGFs，从而调节附近细胞可利用的游离FGF。颅骨中的机械信号传导源于神经颅骨快速扩张期间硬脑膜中产生的张力。在体外对大鼠在第16至24天之间融合的额骨后缝施加周期性张力。观察到颅缝融合时间显著延迟以及FGFR1和2的表达域增加，这表明颅缝通畅性对机械信号敏感，并且FGF系统在介导此类刺激中可能发挥作用。最后，观察到额骨内缝和矢状缝下方硬脑膜的细胞在发育的第10至16天之间发生形态转变为树突状形态，并迁移到颅缝间充质中。这一过程可能参与颅缝和骨的形态发生，并影响沿前后轴的颅缝通畅性。
