TGFβ and BMP Dependent Cell Fate Changes Due to Loss of Filamin B Produces Disc Degeneration and Progressive Vertebral Fusions.
TGFβ and BMP Dependent Cell Fate Changes Due to Loss of Filamin B Produces Disc Degeneration and Progressive Vertebral Fusions.
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DOI：
10.1371/journal.pgen.1005936
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发表时间：
2016-03
期刊：
影响因子：
4.5
通讯作者：
Krakow D
中科院分区：
文献类型：
--
作者：
Zieba J;Forlenza KN;Khatra JS;Sarukhanov A;Duran I;Rigueur D;Lyons KM;Cohn DH;Merrill AE;Krakow D
脊柱腕跗关节骨性结合症（SCT）是一种常染色体隐性遗传疾病，其特征是进行性椎体融合，由细丝蛋白B（FLNB）功能缺失突变引起。FLNB通过连接肌动蛋白细胞骨架与信号转导系统而作为信号传导支架，但SCT的发病机制仍不清楚。采用Flnb基因敲除小鼠，我们发现形态学和分子证据表明，Flnb-/-小鼠的椎间盘（IVD）在出生后发育过程中由于IVD，特别是纤维环（AF）的异常细胞命运变化而发生快速和进行性退化。在Flnb-/-小鼠中，AF细胞失去其典型的成纤维细胞样特征，并获得肥大软骨细胞的分子和表型特征。这种变化的特征是软骨样骨化的标志，包括胶原基质的改变、胶原X的表达、细胞凋亡增加和椎间盘组织的不适当骨化。我们发现，AF细胞向软骨细胞的转化与通过Smad 2/3和BMP诱导的p38信号传导上调的TGFβ信号传导以及经典和非经典靶基因p21和Ctgf的持续激活一致。这些发现表明FLNB参与了TGFβ/BMP信号传导的减弱并影响AF细胞的命运。此外，我们证明了Flnb-/-小鼠的IVD中断类似于老化的退行性椎间盘，并揭示了对椎骨融合和椎间盘退行性变的分子原因的新见解。尽管有大量关于骨骼形成和发育的知识基础，但识别椎间盘（IVD）老化和退变背后的分子变化一直是一个挑战。细丝蛋白B（细胞骨架结构的蛋白质成分）的缺失导致脊柱腕跗关节骨性结合，这是一种罕见的遗传性疾病，其特征是椎体融合。类似地，缺乏细丝蛋白B蛋白的小鼠显示椎体融合。我们发现这些融合是由IVD的早期退变和最终骨化引起的。我们的研究表明，这种变性是由TGFβ和BMP活性增加引起的，这是骨和软骨形成所必需的发育途径。这些发现代表了我们在理解IVD变性的分子基础方面向前迈出的重要一步。以及揭示细丝蛋白B在TGFβ/BMP信号调节中的作用。此外，我们证明了在模式生物中研究罕见疾病脊椎腕跗关节骨性结合可以揭示更常见疾病的潜在机制。最后，我们的研究结果提供了一个模型系统，将有助于进一步发现有关椎间盘退变，这影响了人口的显着比例。
Spondylocarpotarsal synostosis (SCT) is an autosomal recessive disorder characterized by progressive vertebral fusions and caused by loss of function mutations in Filamin B (FLNB). FLNB acts as a signaling scaffold by linking the actin cytoskleteon to signal transduction systems, yet the disease mechanisms for SCT remain unclear. Employing a Flnb knockout mouse, we found morphologic and molecular evidence that the intervertebral discs (IVDs) of Flnb–/–mice undergo rapid and progressive degeneration during postnatal development as a result of abnormal cell fate changes in the IVD, particularly the annulus fibrosus (AF). In Flnb–/–mice, the AF cells lose their typical fibroblast-like characteristics and acquire the molecular and phenotypic signature of hypertrophic chondrocytes. This change is characterized by hallmarks of endochondral-like ossification including alterations in collagen matrix, expression of Collagen X, increased apoptosis, and inappropriate ossification of the disc tissue. We show that conversion of the AF cells into chondrocytes is coincident with upregulated TGFβ signaling via Smad2/3 and BMP induced p38 signaling as well as sustained activation of canonical and noncanonical target genes p21 and Ctgf. These findings indicate that FLNB is involved in attenuation of TGFβ/BMP signaling and influences AF cell fate. Furthermore, we demonstrate that the IVD disruptions in Flnb–/–mice resemble aging degenerative discs and reveal new insights into the molecular causes of vertebral fusions and disc degeneration. Whereas there is a large foundation of knowledge concerning skeletal formation and development, identifying the molecular changes behind Intervertebral Disc (IVD) aging and degeneration has been a challenge. The loss of Filamin B, a protein component of the cell’s cytoskeletal structure, gives rise to Spondylocarpotarsal Synostosis, a rare genetic disorder characterized by fusions of the vertebral bodies. Similarly, mice lacking the Filamin B protein show fusions of the vertebral bodies. We found that these fusions are caused by the early degeneration and eventual ossification of the IVDs. Our study demonstrates that this degeneration is caused by the increase in TGFβ and BMP activity, developmental pathways essential in bone and cartilage formation. These findings represent a significant step forward in our understanding of the molecular basis of IVD degeneration. as well as revealing filamin B’s role in TGFβ/BMP signaling regulation. Moreover, we demonstrate that the study of the rare disease spondylocarpotarsal synostosis in a model organism can uncover mechanisms underlying more common diseases. Finally, our findings provide a model system that will facilitate further discoveries regarding disc degeneration, which affects a significant proportion of the population.