Zieba Jennifer, Forlenza Kimberly Nicole, Khatra Jagteshwar Singh, Sarukhanov Anna, Duran Ivan, Rigueur Diana, Lyons Karen M, Cohn Daniel H, Merrill Amy E, Krakow Deborah
Department of Human Genetics, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, California, United States of America.
Department of Orthopaedic Surgery, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, California, United States of America.
PLoS Genet. 2016 Mar 28;12(3):e1005936. doi: 10.1371/journal.pgen.1005936. eCollection 2016 Mar.
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.
脊椎腕跗骨联合症（SCT）是一种常染色体隐性疾病，其特征为椎体逐渐融合，由细丝蛋白B（FLNB）功能丧失性突变引起。FLNB通过将肌动蛋白细胞骨架与信号转导系统相连，起到信号支架的作用，但SCT的发病机制仍不清楚。利用Flnb基因敲除小鼠，我们发现形态学和分子学证据表明，Flnb基因敲除小鼠的椎间盘（IVD）在出生后发育过程中会迅速且渐进性退变，这是由于IVD尤其是纤维环（AF）中细胞命运异常改变所致。在Flnb基因敲除小鼠中，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。这种变化以内软骨样骨化的特征为特点，包括胶原基质改变、X型胶原表达、细胞凋亡增加以及椎间盘组织的异常骨化。我们发现AF细胞向软骨细胞的转化与通过Smad2/3上调的TGFβ信号、BMP诱导的p38信号以及经典和非经典靶基因p21和Ctgf的持续激活同时发生。这些发现表明FLNB参与TGFβ/BMP信号的减弱，并影响AF细胞命运。此外，我们证明Flnb基因敲除小鼠的IVD破坏类似于衰老退变的椎间盘，并揭示了椎体融合和椎间盘退变分子原因的新见解。
