Altered cytoskeletal organization characterized lethal but not surviving Brtl+/- mice: insight on phenotypic variability in osteogenesis imperfecta
Altered cytoskeletal organization characterized lethal but not surviving Brtl+/- mice: insight on phenotypic variability in osteogenesis imperfecta
复制标题
DOI：
10.1093/hmg/ddv328
复制
发表时间：
2015-11-01
影响因子：
3.5
通讯作者：
Forlino, Antonella
中科院分区：
文献类型：
--
作者：
Bianchi, Laura;Gagliardi, Assunta;Forlino, Antonella
成骨不全症（OI）是一种遗传性骨病，具有显性和隐性传播。其特点是临床结果范围广泛，从非常轻微到围产期致命。在存在相同分子缺陷的情况下，熟悉的 OI 内部和相互之间的表型变异仍然令研究领域感到困惑。我们使用 OI 小鼠模型 Brtl(+/-) 来研究 OI 表型变异的分子基础。 Brtl(+/-) 类似于经典的显性 OI，并显示出与 I 型胶原蛋白的 α 1 链中相同的 Gly349Cys 取代相关的中度严重或致命结果。使用了系统生物学方法。我们利用蛋白质组通路分析将具有不同结果的 Brtl(+/-) 小鼠骨骼和皮肤中差异表达的蛋白质功能联系起来，以定义可能的表型调节剂。皮肤/骨和骨/皮肤混合网络突出了三种焦点蛋白：波形蛋白、stathmin 和 cofilin-1，属于或参与细胞骨架组织。免疫组织化学确实证明异常细胞骨架仅发生在 Brtl(+/-) 致死小鼠的组织中。异常的细胞骨架影响成骨细胞增殖、胶原蛋白沉积、整合素和TGF-β信号传导，从而损害骨结构特性。最后，在从携带相同甘氨酸取代的致死性成纤维细胞中检测到异常的细胞骨架组装，但在非致死性成骨不全患者中未检测到。我们的数据表明，受损的细胞骨架组装会损害突变致死小鼠的细胞信号传导和细胞运输，从而改变骨骼特性。这些结果表明细胞骨架作为表型调节剂和成骨不全治疗的潜在新靶点。
Osteogenesis imperfecta (OI) is a heritable bone disease with dominant and recessive transmission. It is characterized by a wide spectrum of clinical outcomes ranging from very mild to lethal in the perinatal period. The intra- and inter-familiar OI phenotypic variability in the presence of an identical molecular defect is still puzzling to the research field. We used the OI murine model Brtl(+/-) to investigate the molecular basis of OI phenotypic variability. Brtl(+/-) resembles classical dominant OI and shows either a moderately severe or a lethal outcome associated with the same Gly349Cys substitution in the alpha 1 chain of type I collagen. A systems biology approach was used. We took advantage of proteomic pathway analysis to functionally link proteins differentially expressed in bone and skin of Brtl(+/-) mice with different outcomes to define possible phenotype modulators. The skin/bone and bone/skin hybrid networks highlighted three focal proteins: vimentin, stathmin and cofilin-1, belonging to or involved in cytoskeletal organization. Abnormal cytoskeleton was indeed demonstrated by immunohistochemistry to occur only in tissues from Brtl(+/-) lethal mice. The aberrant cytoskeleton affected osteoblast proliferation, collagen deposition, integrin and TGF-beta signaling with impairment of bone structural properties. Finally, aberrant cytoskeletal assembly was detected in fibroblasts obtained from lethal, but not from non-lethal, OI patients carrying an identical glycine substitution. Our data demonstrated that compromised cytoskeletal assembly impaired both cell signaling and cellular trafficking in mutant lethal mice, altering bone properties. These results point to the cytoskeleton as a phenotypic modulator and potential novel target for OI treatment.