Deng Yujie, Wu Ailing, Li Pikshan, Li Gang, Qin Ling, Song Hai, Mak Kinglun Kingston
Stem Cell and Regeneration Thematic Research Program, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China.
Cell Rep. 2016 Mar 8;14(9):2224-2237. doi: 10.1016/j.celrep.2016.02.021. Epub 2016 Feb 25.
Hippo signaling controls organ size and tissue regeneration in many organs, but its roles in chondrocyte differentiation and bone repair remain elusive. Here, we demonstrate that Yap1, an effector of Hippo pathway inhibits skeletal development, postnatal growth, and bone repair. We show that Yap1 regulates chondrocyte differentiation at multiple steps in which it promotes early chondrocyte proliferation but inhibits subsequent chondrocyte maturation both in vitro and in vivo. Mechanistically, we find that Yap1 requires Teads binding for direct regulation of Sox6 expression to promote chondrocyte proliferation. In contrast, Yap1 inhibits chondrocyte maturation by suppression of Col10a1 expression through interaction with Runx2. In addition, Yap1 also governs the initiation of fracture repair by inhibition of cartilaginous callus tissue formation. Taken together, our work provides insights into the mechanism by which Yap1 regulates endochondral ossification, which may help the development of therapeutic treatment for bone regeneration.
河马信号通路在许多器官中控制器官大小和组织再生，但其在软骨细胞分化和骨修复中的作用仍不清楚。在此，我们证明Yap1（河马信号通路的一个效应因子）会抑制骨骼发育、出生后的生长以及骨修复。我们表明，Yap1在多个步骤调节软骨细胞分化，在体外和体内，它促进早期软骨细胞增殖，但抑制随后的软骨细胞成熟。从机制上来说，我们发现Yap1需要与Teads结合以直接调控Sox6表达来促进软骨细胞增殖。相反，Yap1通过与Runx2相互作用抑制Col10a1表达，从而抑制软骨细胞成熟。此外，Yap1还通过抑制软骨痂组织形成来控制骨折修复的起始。综上所述，我们的工作为Yap1调节软骨内成骨的机制提供了见解，这可能有助于骨再生治疗方法的开发。
