Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China ; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beilishi Road, Xicheng District, Beijing, China.
Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China.
PLoS One. 2013 Dec 20;8(12):e83080. doi: 10.1371/journal.pone.0083080. eCollection 2013.
Aberrant proliferation of nucleus pulposus cell is implicated in the pathogenesis of intervertebral disc degeneration. Recent findings revealed that microRNAs, a class of small noncoding RNAs, could regulate cell proliferation in many pathological conditions. Here, we showed that miR-10b was dramatically upregulated in degenerative nucleus pulposus tissues when compared with nucleus pulposus tissues isolated from patients with idiopathic scoliosis. Moreover, miR-10b levels were associated with disc degeneration grade and downregulation of HOXD10. In cultured nucleus pulposus cells, miR-10b overexpression stimulated cell proliferation with concomitant translational inhibition of HOXD10 whereas restored expression of HOXD10 reversed the mitogenic effect of miR-10b. MiR-10b-mediated downregulation of HOXD10 led to increased RhoC expression and Akt phosphorylation. Either knockdown of RhoC or inhibition of Akt abolished the effect of miR-10b on nucleus pulposus cell proliferation. Taken together, aberrant miR-10b upregulation in intervertebral disc degeneration could contribute to abnormal nucleus pulposus cell proliferation through derepressing the RhoC-Akt pathway by targeting HOXD10. Our study also underscores the potential of miR-10b and the RhoC-Akt pathway as novel therapeutic targets in intervertebral disc degeneration.
异常的髓核细胞增殖与椎间盘退变的发病机制有关。最近的研究结果表明，miRNAs 是一类小的非编码 RNA，可以在许多病理条件下调节细胞增殖。在这里，我们发现与特发性脊柱侧凸患者分离的髓核组织相比，退变的髓核组织中 miR-10b 显著上调。此外，miR-10b 水平与椎间盘退变程度和 HOXD10 的下调有关。在培养的髓核细胞中，miR-10b 的过表达刺激细胞增殖，同时翻译抑制 HOXD10，而恢复表达的 HOXD10 逆转了 miR-10b 的促有丝分裂作用。miR-10b 介导的 HOXD10 下调导致 RhoC 表达和 Akt 磷酸化增加。敲低 RhoC 或抑制 Akt 均可消除 miR-10b 对髓核细胞增殖的影响。总之，椎间盘退变中异常的 miR-10b 上调可能通过靶向 HOXD10 来抑制 RhoC-Akt 通路，从而导致异常的髓核细胞增殖。我们的研究还强调了 miR-10b 和 RhoC-Akt 通路作为椎间盘退变的新治疗靶点的潜力。
