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Abstract：
We have recently demonstrated that overexpression of Smurf2 under the control of type II collagen alpha 1 (Col2a1) promoter induces an intervertebral disc degeneration phenotype in Col2a1-Smurf2 transgenic mice. The chondrocyte-like cells that express type II collagen and Smurf2 in the transgenic mouse discs are prone to degenerate. However, how the chondrocyte-like cells contribute to disc degeneration is not known. Here, we utilized primary old bovine nucleus pulposus (NP) cells as substitutes for the chondrocyte-like cells in Col2a1-Smurf2 transgenic mouse discs to identify mechanism. We found that 35% of the cells were senescent; TGF-β treatment of the cells induced a rapid moderate accumulation of β-catenin, which interacted with connective tissue growth factor (CTGF/CCN2) in the cytoplasm and recruited it to the membrane for secretion. The TGF-β-initiated β-catenin-mediated CTGF secretory cascade did not occur in primary young bovine NP cells; however, when Smurf2 was overexpressed in young bovine NP cells, the cells became senescent and allowed this cascade to occur. These results suggest that Smurf2-induced disc degeneration in Col2a1-Smurf2 transgenic mice occurs through activation of CTGF secretory pathway in senescent disc cells.
摘要：
我们最近证明，在II型胶原蛋白α1（Col2a1）启动子的控制下，Smurf2的过表达可诱导Col2a1-Smurf2转基因小鼠的椎间盘退变表型。在转基因小鼠圆盘中表达II型胶原和Smurf2的软骨细胞样细胞倾向于退化。然而,软骨细胞样细胞如何导致椎间盘退变尚不清楚.这里,在Col2a1-Smurf2转基因小鼠椎间盘中,我们利用原代老牛髓核(NP)细胞作为软骨细胞样细胞的替代物,以鉴定其机制.我们发现，35％的细胞是衰老的;TGF-β处理的细胞诱导β-连环蛋白的快速适度积累，它与细胞质中的结缔组织生长因子（CTGF/CCN2）相互作用，并将其募集到膜上进行分泌。TGF-β启动的β-catenin介导的CTGF分泌级联反应在原代年轻的牛NP细胞中没有发生；然而，当Smurf2在年轻的牛NP细胞中过表达时，细胞变得衰老，并允许这种级联发生。这些结果表明，Col2a1-Smurf2转基因小鼠中Smurf2诱导的椎间盘退变是通过激活衰老椎间盘细胞中的CTGF分泌途径而发生的。
