TY - JOUR
T1 - Up-regulation of FOXD1 by yap alleviates senescence and osteoarthritis
AU - Fu, Lina
AU - Hu, Yuqiong
AU - Song, Moshi
AU - Liu, Zunpeng
AU - Zhang, Weiqi
AU - Yu, Fa Xing
AU - Wu, Jun
AU - Wang, Si
AU - Belmonte, Juan Carlos Izpisua
AU - Chan, Piu
AU - Qu, Jing
AU - Tang, Fuchou
AU - Liu, Guang Hui
N1 - Funding Information:
This work was supported by the National Key Research and Development Program of China (2018YFC2000100), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16010100), the National Key Research and Development Program of China (2017YFA0103304, 2017YFA0102802, 2018YFA0107203, 2015CB964800, 2014CB910503), the National Natural Science Foundation of China (91749202, 81625009, 31671429, 91749123, 81330008, 81601233, 81671377, 31601109, 31601158, 81771515, 81701388, 81870228, 81822018, 81801399, 31801010, 81801370 and 81861168034), Program of Beijing Municipal Science and Technology Commission (Z151100003915072), Beijing Municipal Commission of Health and Family Planning (PXM2018_026283_000002), Advanced Innovation Center for Human Brain Protection (3500-1192012) and the State Key Laboratory of Membrane Biology. Work in the laboratory of J.C.I. B. was supported by the G. Harold and Leila Y. Mathers Charitable Foundation, the Glenn Foundation, Fundacion Dr. Pedro Guillen and Universidad Catolica San Antonio de Murcia (UCAM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2019 Fu et al.
PY - 2019/4
Y1 - 2019/4
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pbio.3000201
DO - 10.1371/journal.pbio.3000201
M3 - Article
C2 - 30933975
AN - SCOPUS:85064723096
SN - 1544-9173
VL - 17
JO - PLoS biology
JF - PLoS biology
IS - 4
M1 - e3000201
ER -