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

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101183755 Publication Model: eCollection Cited Medium: Internet ISSN: 1545-7885 (Electronic) Linking ISSN: 15449173 NLM ISO Abbreviation: PLoS Biol Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science, [2003]-

Adaptor Proteins, Signal Transducing/*metabolism ; Forkhead Transcription Factors/*metabolism ; Osteoarthritis/*metabolism ; Osteoarthritis/*pathology ; Transcription Factors/*metabolism; Adaptor Proteins, Signal Transducing/genetics ; Animals ; Cell Proliferation/genetics ; Cellular Senescence/physiology ; Forkhead Transcription Factors/genetics ; Heterografts ; Humans ; Male ; Mesenchymal Stem Cells/metabolism ; Mesenchymal Stem Cells/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Inbred NOD ; Mice, SCID ; Osteoarthritis/genetics ; Signal Transduction ; Transcription Factors/genetics ; Transcriptional Activation ; Up-Regulation ; YAP-Signaling Proteins

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.
Competing Interests: The authors have declared that no competing interests exist.

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0 (Adaptor Proteins, Signal Transducing)
0 (FOXD1 protein, human)
0 (Forkhead Transcription Factors)
0 (Transcription Factors)
0 (YAP-Signaling Proteins)
0 (YAP1 protein, human)

Date Created: 20190402 Date Completed: 20200106 Latest Revision: 20211204

20240628

PMC6459557

10.1371/journal.pbio.3000201

30933975