Wu Qiuqian, Mathers Chun, Wang Ernest W, Sheng Sen, Wenkert David, Huang Jason H
Department of Neurosurgery Institute for Translational Medicine Baylor Scott & White Health Temple TX USA.
Division of Endocrinology Baylor Scott & White Health Temple TX USA.
JBMR Plus. 2018 Jul 10;3(2):e10069. doi: 10.1002/jbm4.10069. eCollection 2019 Feb.
We have recently demonstrated that overexpression of Smurf2 under the control of type II collagen alpha 1 () promoter induces an intervertebral disc degeneration phenotype in 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 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 transgenic mice occurs through activation of CTGF secretory pathway in senescent disc cells.
我们最近证明，在II型胶原蛋白α1（）启动子控制下Smurf2的过表达在转基因小鼠中诱导了椎间盘退变表型。在转基因小鼠椎间盘中表达II型胶原蛋白和Smurf2的软骨样细胞易于退变。然而，软骨样细胞如何导致椎间盘退变尚不清楚。在这里，我们利用原代老龄牛髓核（NP）细胞替代转基因小鼠椎间盘中的软骨样细胞来确定机制。我们发现35%的细胞衰老；用转化生长因子-β（TGF-β）处理这些细胞会诱导β-连环蛋白迅速适度积累，β-连环蛋白在细胞质中与结缔组织生长因子（CTGF/CCN2）相互作用，并将其招募到细胞膜进行分泌。TGF-β启动的β-连环蛋白介导的CTGF分泌级联反应在原代年轻牛NP细胞中未发生；然而，当Smurf2在年轻牛NP细胞中过表达时，细胞衰老并允许该级联反应发生。这些结果表明，Smurf2诱导的转基因小鼠椎间盘退变是通过衰老椎间盘细胞中CTGF分泌途径的激活而发生的。
