Yes-associated protein nuclear translocation promotes anabolic activity in human articular chondrocytes

Y. Cui, M. Z. Miao, M. Wang, Q. P. Su, K. Qiu, L. Arbeeva, S. Chubinskaya, B. O. Diekman, R. F. Loeser

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Objective: Yes-associated protein (YAP) has been widely studied as a mechanotransducer in many cell types, but its function in cartilage is controversial. The aim of this study was to identify the effect of YAP phosphorylation and nuclear translocation on the chondrocyte response to stimuli relevant to osteoarthritis (OA). Design: Cultured normal human articular chondrocytes from 81 donors were treated with increased osmolarity media as an in vitro model of mechanical stimulation, fibronectin fragments (FN-f) or IL-1β as catabolic stimuli, and IGF-1 as an anabolic stimulus. YAP function was assessed with gene knockdown and inhibition by verteporfin. Nuclear translocation of YAP and its transcriptional co-activator TAZ and site-specific YAP phosphorylation were determined by immunoblotting. Immunohistochemistry and immunofluorescence to detect YAP were performed on normal and OA human cartilage with different degrees of damage. Results: Chondrocyte YAP/TAZ nuclear translocation increased under physiological osmolarity (400 mOsm) and IGF-1 stimulation, which was associated with YAP phosphorylation at Ser128. In contrast, catabolic stimulation decreased the levels of nuclear YAP/TAZ through YAP phosphorylation at Ser127. Following YAP inhibition, anabolic gene expression and transcriptional activity decreased. Additionally, YAP knockdown reduced proteoglycan staining and levels of type II collagen. Total YAP immunostaining was greater in OA cartilage, but YAP was sequestered in the cytosol in cartilage areas with more severe damage. Conclusions: YAP chondrocyte nuclear translocation is regulated by differential phosphorylation in response to anabolic and catabolic stimuli. Decreased nuclear YAP in OA chondrocytes may contribute to reduced anabolic activity and promotion of further cartilage loss.

Original languageEnglish (US)
Pages (from-to)1078-1090
Number of pages13
JournalOsteoarthritis and Cartilage
Volume31
Issue number8
DOIs
StatePublished - Aug 2023
Externally publishedYes

Keywords

  • Chondrocytes
  • Differential phosphorylation
  • Mechanotransduction
  • Nuclear translocation
  • Yes-associated protein

ASJC Scopus subject areas

  • Rheumatology
  • Biomedical Engineering
  • Orthopedics and Sports Medicine

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