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 - 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 -