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PLoS Biol. 2019 Apr 1;17(4):e3000201. doi: 10.1371/journal.pbio.3000201. eCollection 2019 Apr.

Up-regulation of FOXD1 by YAP alleviates senescence and osteoarthritis.

Fu L1,2,3, Hu Y4,5, Song M3,6,7, Liu Z2,3, Zhang W1,3,7,8, Yu FX9, Wu J10, Wang S1,8, Izpisua Belmonte JC11, Chan P8, Qu J2,3,7, Tang F4,5,12,13, Liu GH1,3,6,7,8,14.

Author information

National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
University of Chinese Academy of Sciences, Beijing, China.
Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Peking University, Beijing, China.
Biomedical Pioneering Innovation Center, Peking University, Beijing, China.
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, China.
Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, United States of America.
Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing, China.
Beijing Institute for Brain Disorders, Beijing, China.


Cellular senescence is a driver of various aging-associated disorders, including osteoarthritis. Here, we identified a critical role for Yes-associated protein (YAP), a major effector of Hippo signaling, in maintaining a younger state of human mesenchymal stem cells (hMSCs) and ameliorating osteoarthritis in mice. Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR associated protein 9 nuclease (Cas9)-mediated knockout (KO) of YAP in hMSCs resulted in premature cellular senescence. Mechanistically, YAP cooperated with TEA domain transcriptional factor (TEAD) to activate the expression of forkhead box D1 (FOXD1), a geroprotective protein. YAP deficiency led to the down-regulation of FOXD1. In turn, overexpression of YAP or FOXD1 rejuvenated aged hMSCs. Moreover, intra-articular administration of lentiviral vector encoding YAP or FOXD1 attenuated the development of osteoarthritis in mice. Collectively, our findings reveal YAP-FOXD1, a novel aging-associated regulatory axis, as a potential target for gene therapy to alleviate osteoarthritis.

Conflict of interest statement

The authors have declared that no competing interests exist.

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