Fibronectin (FN) serves as a critical organizer of extracellular matrix networks in two principal isoforms, the plasma FN and the cellular FN. While FN's pivotal role in various organ systems, including the blood vasculature, is well-established, its contribution to the development of the skeletal system is much less explored. Furthermore, the pathomechanisms of spondyloepiphyseal dysplasia caused by FN mutations remain elusive. In this minireview, we discuss findings from our recent two studies using i) an iPSC-based cell culture model to explore how FN mutations in spondyloepiphyseal dysplasia impact mesenchymal cell differentiation into chondrocytes and ii) conditional FN knockout mouse models to determine the physiological roles of FN isoforms during postnatal skeletal development. The data revealed that FN mutations cause severe intracellular and matrix defects in mesenchymal cells and impair their ability to differentiate into chondrocytes. The findings further demonstrate the important roles of both FN isoforms in orchestrating regulated chondrogenesis during skeletal development. We critically discuss the findings in the context of the existing literature.

中文翻译：

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纤连蛋白在骨骼形态发生和发病机制中的重要作用


纤连蛋白 （FN） 在血浆 FN 和细胞 FN 两种主要亚型中充当细胞外基质网络的关键组织者。虽然 FN 在各种器官系统（包括血液管系统）中的关键作用已得到公认，但它对骨骼系统发育的贡献却鲜为人知。此外，FN 突变引起的脊椎骨骺发育不良的病理机制仍然难以捉摸。在这篇小型综述中，我们讨论了我们最近的两项研究的结果，使用 i） 基于 iPSC 的细胞培养模型来探索脊椎骨骺发育不良中的 FN 突变如何影响间充质细胞分化为软骨细胞，以及 ii） 条件性 FN 敲除小鼠模型来确定 FN 亚型在出生后骨骼发育过程中的生理作用。数据显示，FN 突变会导致间充质细胞出现严重的细胞内和基质缺陷，并损害它们分化为软骨细胞的能力。研究结果进一步证明了两种 FN 亚型在骨骼发育过程中协调受调节的软骨生成中的重要作用。我们在现有文献的背景下批判性地讨论了这些发现。