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首页> 外文期刊>Cell and Tissue Research >Establishment of fibrillin-deficient osteoprogenitor cell lines identifies molecular abnormalities associated with extracellular matrix perturbation of osteogenic differentiation.
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Establishment of fibrillin-deficient osteoprogenitor cell lines identifies molecular abnormalities associated with extracellular matrix perturbation of osteogenic differentiation.

机译：缺乏原纤维蛋白的骨祖细胞系的建立鉴定了与成骨分化的细胞外基质扰动有关的分子异常。

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摘要

Fibrillin-1 and fibrillin-2 are structural components of the extracellular matrix which are also involved in modulating local TGFbeta and BMP bioavailability. Loss of fibrillin-1 or fibrillin-2 is associated with perturbed osteoblast maturation principally as the result of unbalanced TGFbeta and BMP signaling. Here, we demonstrated that stable expression of small hairpin RNAs against fibrillin-1(Fbn1) or fibrillin-2 (Fbn2) transcripts in the clonal osteoprogenitor cell line Kusa-A1 led to the same phenotypic and molecular manifestations as germline Fbn1- or Fbn2-null mutations in primary calvarial osteoblast cultures. Proof-of-concept experiments are also presented showing that Fbn1- or Fbn2-silenced Kusa-A1 cell lines are suitable models to identify candidate determinants of osteogenesis which are under the control of extracellular microfibrils. Specific findings included: the inference of a potential role for fibrillin-1-mediated cell-matrix interactions in regulating Kusa-A1 proliferation; the possibility of fibrillin-2 involvement in modulating the activity of transcription factor Runx2 by restricting microRNA expression and/or processing; and the suggestion that fibrillin-1 and fibrillin-2 influence Notch signaling indirectly by differentially regulating BMP signaling. Collectively, the data reiterated the notion that fibrillin-1 and fibrillin-2 exert opposite effects on osteoblast differentiation through the discrete modulation of a broad network of interacting signaling molecules.
机译：Fibrillin-1和Fibrillin-2是细胞外基质的结构成分，它们也参与调节局部TGFbeta和BMP的生物利用度。原发性TGFbeta和BMP信号失衡的结果是，原纤维蛋白-1或原纤维蛋白-2的丢失与成骨细胞的成熟扰动有关。在这里，我们证明了在克隆的骨祖细胞系Kusa-A1中针对纤维蛋白1（Fbn1）或纤维蛋白2（Fbn2）转录本的小发夹RNA的稳定表达导致与种系Fbn1-或Fbn2-相同的表型和分子表现原发颅盖骨成骨细胞培养中的空突变。还提出了概念验证实验，表明Fbn1或Fbn2沉默的Kusa-A1细胞系是鉴定在细胞外微纤维控制下成骨作用候选决定因素的合适模型。具体发现包括：推断原纤维蛋白1介导的细胞-基质相互作用在调节Kusa-A1增殖中的潜在作用;通过限制microRNA的表达和/或加工，原纤维蛋白2参与调节转录因子Runx2活性的可能性;提示原纤维蛋白-1和原纤维蛋白-2通过差异调节BMP信号传导间接影响Notch信号传导。总体而言，数据重申了这样的观念，即通过相互作用信号分子的广泛网络的离散调节，原纤维蛋白-1和原纤维蛋白-2对成骨细胞的分化产生相反的作用。

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