Up-regulation of FOXD1 by YAP alleviates senescence and osteoarthritis

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

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Adaptor Proteins, Signal Transducing
  • FOXD1 protein, human
  • Forkhead Transcription Factors
  • Transcription Factors
  • YAP1 protein, human

Grant support

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.