Brd4 is required for chondrocyte differentiation and endochondral ossification

Christopher R. Paradise, M. Lizeth Galvan, Oksana Pichurin, Sofia Jerez, Eva Kubrova, S. Sharare Dehghani, Margarita E. Carrasco, Roman Thaler, A. Noelle Larson, Andre J. van Wijnen*, Amel Dudakovic

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

13 Citations (Scopus)

Abstract

Differentiation of multi-potent mesenchymal stromal cells (MSCs) is directed by the activities of lineage-specific transcription factors and co-factors. A subset of these proteins controls the accessibility of chromatin by recruiting histone acetyl transferases or deacetylases that regulate acetylation of the N-termini of H3 and H4 histone proteins. Bromodomain (BRD) proteins recognize these acetylation marks and recruit the RNA pol II containing transcriptional machinery. Our previous studies have shown that Brd4 is required for osteoblast differentiation in vitro. Here, we investigated the role of Brd4 on endochondral ossification in C57BL/6 mice and chondrogenic differentiation in cell culture models. Conditional loss of Brd4 in the mesenchyme (Brd4 cKO, Brd4fl/fl: Prrx1-Cre) yields smaller mice that exhibit alteration in endochondral ossification. Importantly, abnormal growth plate morphology and delayed long bone formation is observed in juvenile Brd4 cKO mice. One week old Brd4 cKO mice have reduced proliferative and hypertrophic zones within the physis and exhibit a delay in the formation of the secondary ossification center. At the cellular level, Brd4 function is required for chondrogenic differentiation and maturation of both ATDC5 cells and immature mouse articular chondrocytes. Mechanistically, Brd4 loss suppresses Sox9 levels and reduces expression of Sox9 and Runx2 responsive endochondral genes (e.g., Col2a1, Acan, Mmp13 and Sp7/Osx). Collectively, our results indicate that Brd4 is a key epigenetic regulator required for normal chondrogenesis and endochondral ossification.

Original languageEnglish
Article number116234
JournalBone
Volume154
DOIs
Publication statusPublished - Jan 2022

Bibliographical note

Funding Information:
We thank our Mayo Clinic colleagues and members of the Orthopedic Research Laboratories, including Drs. Jennifer Westendorf, Wenchun Qu, and David Deyle for stimulating discussions and sharing reagents. We also thank Dr. Anup Dey and Dr. Keiko Ozato at the National Institutes of Health (Bethesda, MD) for providing the conditional knockout mouse model central to these studies. We acknowledge the assistance from the Biomaterials Characterization and Quantitative Histomorphometry Core Facility as well as the X-ray Imaging (XRI) Core Facility at Mayo Clinic. All studies were done at Mayo Clinic. This publication was made possible through an intramural award from Mayo Clinic (Career Development Award in Orthopedics Research to AD) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR049069 to AJvW). We also thank William and Karen Eby for generous philanthropic support. The data that support the findings of this study are available in Gene Expression Omnibus (GEO) database at https://www.ncbi.nlm.nih.gov/geo/, Accession # GSE97118. ANL performed consulting with funds directed to research for Globus, Medtronic, Orthopediatrics, and Depuy. ANL holds a patent on anterior vertebral body tethering cord. Other authors have no disclosures to report.

Funding Information:
All studies were done at Mayo Clinic. This publication was made possible through an intramural award from Mayo Clinic (Career Development Award in Orthopedics Research to AD) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases ( R01 AR049069 to AJvW). We also thank William and Karen Eby for generous philanthropic support.

Publisher Copyright:
© 2021

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