Skeletal cell YAP and TAZ combinatorially promote bone development

Christopher D. Kegelman, Devon E. Mason, James H. Dawahare, Daniel J. Horan, Genevieve D. Vigil, Scott S. Howard, Alexander G. Robling, Teresita M. Bellido, Joel D. Boerckel

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

The functions of the paralogous transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-bindingmotif (TAZ) in bone are controversial. Each has been observed to promote or inhibit osteogenesis invitro, with reports of both equivalent and divergent functions. Their combinatorial roles in bone physiology are unknown. We report that combinatorial YAP/TAZ deletion from skeletal lineage cells, using Osterix-Cre, caused an osteogenesis imperfecta-like phenotype with severity dependent on allele dose and greater phenotypic expressivity with homozygous TAZ vs. YAP ablation. YAP/TAZ deletion decreased bone accrual and reduced intrinsic bone material properties through impaired collagen content and organization. These structural and material defects produced spontaneous fractures, particularly in mice with homozygous TAZ deletion and caused neonatal lethality in dual homozygous knockouts. At the cellular level in vivo, YAP/TAZ ablation reduced osteoblast activity and increased osteoclast activity, inanallele dose-dependent manner, impairing bone accrual and remodeling. Transcriptionally, YAP/TAZ deletion and small-molecule inhibition of YAP/TAZ interaction with the transcriptional coeffector TEADreduced osteogenic and collagen-related gene expression, both in vivo and in vitro. These data demonstrate that YAP and TAZ combinatorially promote bone development through regulation of osteoblast activity, matrix quality, and osteoclastic remodeling.

Original languageEnglish (US)
Pages (from-to)2706-2721
Number of pages16
JournalFASEB Journal
Volume32
Issue number5
DOIs
StatePublished - May 2018

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Keywords

  • Osteoblasts
  • Osteogenesis
  • Osteoprogenitor cells
  • Transcriptional regulation

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Kegelman, C. D., Mason, D. E., Dawahare, J. H., Horan, D. J., Vigil, G. D., Howard, S. S., Robling, A. G., Bellido, T. M., & Boerckel, J. D. (2018). Skeletal cell YAP and TAZ combinatorially promote bone development. FASEB Journal, 32(5), 2706-2721. https://doi.org/10.1096/fj.201700872R