Histone deacetylase 3 supports endochondral bone formation by controlling cytokine signaling and matrix remodeling

Lomeli R. Carpio, Elizabeth W. Bradley, Meghan E. McGee-Lawrence, Megan M. Weivoda, Daniel D. Poston, Amel Dudakovic, Ming Xu, Tamar Tchkonia, James L. Kirkland, Andre J. Van Wijnen, Merry Jo Oursler, Jennifer J. Westendorf

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52 Scopus citations


Histone deacetylase (HDAC) inhibitors are efficacious epigenetic-based therapies for some cancers and neurological disorders; however, each of these drugs inhibits multiple HDACs and has detrimental effects on the skeleton. To better understand how HDAC inhibitors affect endochondral bone formation, we conditionally deleted one of their targets, Hdac3, pre- and postnatally in type II collagen a1 (Col2a1)-expressing chondrocytes. Embryonic deletion was lethal, but postnatal deletion of Hdac3 delayed secondary ossification center formation, altered maturation of growth plate chondrocytes, and increased osteoclast activity in the primary spongiosa. HDAC3-deficient chondrocytes exhibited increased expression of cytokine and matrix-degrading genes (Il-6, Mmp3, Mmp13, and Saa3) and a reduced abundance of genes related to extracellular matrix production, bone development, and ossification (Acan, Col2a1, Ihh, and Col10a1). Histone acetylation increased at and near genes that had increased expression. The acetylation and activation of nuclear factor κB (NF-κB) were also increased in HDAC3-deficient chondrocytes. Increased cytokine signaling promoted autocrine activation of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and NF-κB pathways to suppress chondrocyte maturation, as well as paracrine activation of osteoclasts and bone resorption. Blockade of interleukin-6 (IL-6)-JAK-STAT signaling, NF-κB signaling, and bromodomain extraterminal proteins, which recognize acetylated lysines and promote transcriptional elongation, significantly reduced Il-6 and Mmp13 expression in HDAC3-deficient chondrocytes and secondary activation in osteoclasts. The JAK inhibitor ruxolitinib also reduced osteoclast activity in Hdac3 conditional knockout mice. Thus, HDAC3 controls the temporal and spatial expression of tissue-remodeling genes and inflammatory responses in chondrocytes to ensure proper endochondral ossification during development.

Original languageEnglish (US)
Article numberra79
JournalScience signaling
Issue number440
StatePublished - Aug 9 2016

Bibliographical note

Funding Information:
We would like to thank J.-H. Lee, X. Li, O. Pichurin, D. Razidlo, and B. Stensgard for technical assistance. We are grateful to K. Gaonka for bioinformatics assistance and D. Larson for statistical help. We thank T. Ordog for helpful discussions. Funding: This work was supported by research and training grants from the NIH (R01 AR68103, R01 AR065402, R01 AR049069, R01 AR067129, R01 066101, R01 AG048388, R01 AG013925, T32 AR56950, F31 AR067646, K01 AR65397, and F32 AR066508), the Ted Nash Foundation, the Connor Group, the charitable foundation of William and Karen Eby, and Mayo Clinic (Kogod Center for Aging, Center for Biomedical Discovery, and Center for Regenerative Medicine). Author contributions: L.R.C., E.W.B., and J.W.W. conceived and designed experiments. L.R.C., E.W.B., M.E.M.-L., and D.D.P. performed experiments. L.R.C., E.W.B., M.E.M.-L., M.M.W., D.D.P., A.D., M.X., T.T., J.L.K., A.J.v.W., M.J.O., and J.J.W. analyzed data and contributed to critical discussions. L.R.C., A.J.v.W., and J.J.W. wrote and edited the article. Competing interests: The authors declare that they have no competing interests. Data and materials availability: Complete RNA-seq data sets are available at the Gene Expression Omnibus (GSE75549). H3K27ac ChIP-seq data sets are available at the Gene Expression Omnibus (GSE75547).


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