YAP-mediated regulation of the chondrogenic phenotype in response to matrix elasticity

J Mol Histol. 2013 Oct;44(5):587-95. doi: 10.1007/s10735-013-9502-y. Epub 2013 Mar 30.

Abstract

Matrix elasticity exerts considerable influence on the phenotype of terminally differentiated chondrocytes via physical cues. The Yes-associated protein (YAP) transcription co-activator is recognized as a key mediator that may be involved in the nuclear transduction of physical cues controlling cellular behavior and function. However, whether substrate elasticity in the regulation of the chondrocyte phenotype is associated with YAP remains unclear. In this work, we developed micropatterned substrates with varying stiffnesses to investigate the function of YAP and its related Hippo pathway kinases in the regulation of chondrocyte phenotype on soft and stiff substrates. We found that the phenotypic variation of chondrocytes in response to substrate stiffness is concomitant with the changes in YAP localization. The downregulation of YAP expression helps to maintain the chondrogenic phenotype while inhibiting chondrocyte proliferation. Furthermore, the change in the chondrocyte phenotype response to LATS1 kinase inactivation in the Hippo pathway varies significantly between soft and stiff substrates. We also found that LATS1 kinase inactivation promotes chondrocyte dedifferentiation only on stiff substrate. Collectively, these findings reveal that YAP may be involved in the changes that occur in chondrocytes cultured on substrates with different stiffnesses and that these changes do not entirely depend on the Hippo pathway kinase LATS1. Importantly, our findings indicate that YAP inactivation is conducive to the maintenance of the chondrogenic phenotype, thereby providing new insight into articular cartilage repair and regeneration mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylic Resins / chemistry
  • Animals
  • Apoptosis Regulatory Proteins / antagonists & inhibitors
  • Apoptosis Regulatory Proteins / genetics*
  • Apoptosis Regulatory Proteins / metabolism
  • Cartilage, Articular / cytology
  • Cartilage, Articular / metabolism*
  • Cell Proliferation
  • Chondrocytes / cytology
  • Chondrocytes / metabolism*
  • Dimethylpolysiloxanes / chemistry
  • Elasticity
  • Gene Expression Regulation*
  • Hardness
  • Male
  • Phenotype
  • Primary Cell Culture
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism
  • Signal Transduction

Substances

  • Acrylic Resins
  • Apoptosis Regulatory Proteins
  • Dimethylpolysiloxanes
  • RNA, Small Interfering
  • SOX9 Transcription Factor
  • Yap1 protein, rat
  • polyacrylamide gels
  • baysilon
  • Protein-Serine-Threonine Kinases