Yap1 Regulates Multiple Steps of Chondrocyte Differentiation during Skeletal Development and Bone Repair

Cell Rep. 2016 Mar 8;14(9):2224-2237. doi: 10.1016/j.celrep.2016.02.021. Epub 2016 Feb 25.

Abstract

Hippo signaling controls organ size and tissue regeneration in many organs, but its roles in chondrocyte differentiation and bone repair remain elusive. Here, we demonstrate that Yap1, an effector of Hippo pathway inhibits skeletal development, postnatal growth, and bone repair. We show that Yap1 regulates chondrocyte differentiation at multiple steps in which it promotes early chondrocyte proliferation but inhibits subsequent chondrocyte maturation both in vitro and in vivo. Mechanistically, we find that Yap1 requires Teads binding for direct regulation of Sox6 expression to promote chondrocyte proliferation. In contrast, Yap1 inhibits chondrocyte maturation by suppression of Col10a1 expression through interaction with Runx2. In addition, Yap1 also governs the initiation of fracture repair by inhibition of cartilaginous callus tissue formation. Taken together, our work provides insights into the mechanism by which Yap1 regulates endochondral ossification, which may help the development of therapeutic treatment for bone regeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • Cell Cycle Proteins
  • Cell Differentiation*
  • Cell Proliferation
  • Cells, Cultured
  • Chondrocytes / physiology*
  • Female
  • Femur / growth & development
  • Femur / physiopathology
  • Fracture Healing
  • Gene Expression Regulation
  • Mice, Transgenic
  • Osteogenesis*
  • Phosphoproteins / physiology*
  • Protein Binding
  • SOXD Transcription Factors / genetics
  • SOXD Transcription Factors / metabolism
  • Signal Transduction

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Phosphoproteins
  • SOXD Transcription Factors
  • Sox6 protein, mouse
  • Yap protein, mouse