Section of Orthodontics, Division of Growth and Development, School of Dentistry, University of California, Los Angeles, California; Department of Orthodontics, Peking University, School and Hospital of Stomatology, Beijing, People's Republic of China.
Section of Orthodontics, Division of Growth and Development, School of Dentistry, University of California, Los Angeles, California.
Am J Pathol. 2018 Feb;188(2):392-403. doi: 10.1016/j.ajpath.2017.09.020. Epub 2017 Nov 11.
The pro-chondrogenic function of runt-related transcription factor 2 (Runx2) was previously considered to be dependent on direct binding with the promoter of Indian hedgehog (Ihh)-the major regulator of chondrocyte differentiation, proliferation, and maturation. The authors' previous studies identified neural EGFL like 1 (Nell-1) as a Runx2-responsive growth factor for chondrogenic differentiation and maturation. In this study, it was further revealed that the pro-chondrogenic activities of Nell-1 also rely on Ihh signaling, by showing: i) Nell-1 significantly elevated Ihh signal transduction; ii) Nell-1 deficiency markedly reduced Ihh activation in chondrocytes; and iii) Nell-1-stimulated chondrogenesis was significantly reduced by the specific hedgehog inhibitor cyclopamine. Importantly, the authors demonstrated that Nell-1-responsive Ihh signaling and chondrogenic differentiation extended to Runx2 models in vitro and in vivo. In Runx2 chondrocytes, Nell-1 stimulated the expression and signal transduction of Runx3, another transcription factor required for complete chondrogenic differentiation and maturation. Furthermore, knocking down Runx3 in Runx2 chondrocytes abolished Nell-1's stimulation of Ihh-associated molecule expression, which validates Runx3 as a major mediator of Nell-1-stimulated Ihh activation. For the first time, the Runx2→Nell-1→Runx3→Ihh signaling cascade during chondrogenic differentiation and maturation has been identified as an alternative, but critical, pathway for Runx2 to function as a pro-chondrogenic molecule via Nell-1.
先前认为 runt 相关转录因子 2 (Runx2) 的促软骨形成功能依赖于与 Indian hedgehog (Ihh)-主要调节软骨细胞分化、增殖和成熟的因子-启动子的直接结合。作者之前的研究确定了神经 EGFL 样 1 (Nell-1) 是一种 Runx2 反应性生长因子，可促进软骨细胞的分化和成熟。在这项研究中，作者进一步揭示了 Nell-1 的促软骨形成活性也依赖于 Ihh 信号通路，具体表现为：i）Nell-1 显著增加了 Ihh 信号转导；ii）Nell-1 缺陷显著降低了软骨细胞中的 Ihh 激活；iii）特异性 hedgehog 抑制剂 cyclopamine 显著降低了 Nell-1 刺激的软骨生成。重要的是，作者证明了 Nell-1 反应性的 Ihh 信号通路和软骨分化在体外和体内的 Runx2 模型中得到延伸。在 Runx2 软骨细胞中，Nell-1 刺激了另一种转录因子 Runx3 的表达和信号转导，Runx3 是完全软骨分化和成熟所必需的。此外，在 Runx2 软骨细胞中敲低 Runx3 会消除 Nell-1 对 Ihh 相关分子表达的刺激，这验证了 Runx3 是 Nell-1 刺激 Ihh 激活的主要介质。首次鉴定出 Runx2→Nell-1→Runx3→Ihh 信号级联在软骨分化和成熟过程中作为 Runx2 通过 Nell-1 发挥促软骨形成分子作用的替代但关键途径。
