Skeletal cell YAP and TAZ combinatorially promote bone development

The FASEB JournalVolume 32, Issue 5 p. 2706-2721 ResearchFree to Read Skeletal cell YAP and TAZ combinatorially promote bone development Christopher D. Kegelman, Christopher D. Kegelman Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USASearch for more papers by this authorDevon E. Mason, Devon E. Mason Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USASearch for more papers by this authorJames H. Dawahare, James H. Dawahare Department of Aerospace and Mechanical EngineeringSearch for more papers by this authorDaniel J. Horan, Daniel J. Horan Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, USASearch for more papers by this authorGenevieve D. Vigil, Genevieve D. Vigil Department of Electrical Engineering, University of Notre Dame, Notre Dame, Indiana, USASearch for more papers by this authorScott S. Howard, Scott S. Howard Department of Electrical Engineering, University of Notre Dame, Notre Dame, Indiana, USASearch for more papers by this authorAlexander G. Robling, Alexander G. Robling Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, USASearch for more papers by this authorTeresita M. Bellido, Teresita M. Bellido Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, USASearch for more papers by this authorJoel D. Boerckel, Corresponding Author Joel D. Boerckel boerckel@pennmedicine.upenn.edu Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USACorrespondence: G10A Stemmler Hall, 3450 Hamilton Walk, University of Pennsylvania, Philadelphia, PA 19104, USA. E-mail: boerckel@pennmedicine.upenn.eduSearch for more papers by this author Christopher D. Kegelman, Christopher D. Kegelman Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USASearch for more papers by this authorDevon E. Mason, Devon E. Mason Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USASearch for more papers by this authorJames H. Dawahare, James H. Dawahare Department of Aerospace and Mechanical EngineeringSearch for more papers by this authorDaniel J. Horan, Daniel J. Horan Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, USASearch for more papers by this authorGenevieve D. Vigil, Genevieve D. Vigil Department of Electrical Engineering, University of Notre Dame, Notre Dame, Indiana, USASearch for more papers by this authorScott S. Howard, Scott S. Howard Department of Electrical Engineering, University of Notre Dame, Notre Dame, Indiana, USASearch for more papers by this authorAlexander G. Robling, Alexander G. Robling Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, USASearch for more papers by this authorTeresita M. Bellido, Teresita M. Bellido Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, USASearch for more papers by this authorJoel D. Boerckel, Corresponding Author Joel D. Boerckel boerckel@pennmedicine.upenn.edu Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USACorrespondence: G10A Stemmler Hall, 3450 Hamilton Walk, University of Pennsylvania, Philadelphia, PA 19104, USA. E-mail: boerckel@pennmedicine.upenn.eduSearch for more papers by this author First published: 10 January 2018 https://doi.org/10.1096/fj.201700872RCitations: 13Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract The functions of the paralogous transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in bone are controversial. Each has been observed to promote or inhibit osteogenesis in vitro, 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, in an allele dose-dependent manner, impairing bone accrual and remodeling. Transcriptionally, YAP/TAZ deletion and small-molecule inhibition of YAP/TAZ interaction with the transcriptional coeff ector TEAD reduced 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.—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. Skeletal cell YAP and TAZ combinatorially promote bone development. FASEB J. 32, 2706–2721 (2018). www.fasebj.org Citing Literature Supporting Information Filename Description fsb2fj201700872r-sup-0001.docxapplication/docx, 199.7 KB Supplementary Material fsb2fj201700872r-sup-0002.tifapplication/tif, 4.7 MB Supplementary Material fsb2fj201700872r-sup-0003.tifapplication/tif, 1.2 MB Supplementary Material fsb2fj201700872r-sup-0004.tifapplication/tif, 1.7 MB Supplementary Material fsb2fj201700872r-sup-0005.tifapplication/tif, 891.8 KB Supplementary Material fsb2fj201700872r-sup-0006.tifapplication/tif, 761.8 KB Supplementary Material fsb2fj201700872r-sup-0007.tifapplication/tif, 2.3 MB Supplementary Material fsb2fj201700872r-sup-0008.tifapplication/tif, 544.7 KB Supplementary Material fsb2fj201700872r-sup-0009.tifapplication/tif, 270.1 KB Supplementary Material fsb2fj201700872r-sup-0010.tifapplication/tif, 602.6 KB Supplementary Material Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume32, Issue5May 2018Pages 2706-2721 RelatedInformation