Title | Histone deacetylase 3 supports endochondral bone formation by controlling cytokine signaling and matrix remodeling. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Carpio LR, Bradley EW, McGee-Lawrence ME, Weivoda MM, Poston DD, Dudakovic A, Xu M, Tchkonia T, Kirkland JL, van Wijnen AJ, Oursler MJo, Westendorf JJ |
Journal | Sci Signal |
Volume | 9 |
Issue | 440 |
Pagination | ra79 |
Date Published | 2016 08 09 |
ISSN | 1937-9145 |
Keywords | Animals, Autocrine Communication, Chondrocytes, Extracellular Matrix, Extracellular Matrix Proteins, Histone Deacetylases, Interleukin-6, Janus Kinases, Mice, Mice, Knockout, Osteoclasts, Osteogenesis, Pyrazoles, Signal Transduction |
Abstract | 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 α1 (Col2α1)-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. |
DOI | 10.1126/scisignal.aaf3273 |
Alternate Journal | Sci Signal |
PubMed ID | 27507649 |
PubMed Central ID | PMC5409103 |
Grant List | F32 AR066508 / AR / NIAMS NIH HHS / United States R01 AR067129 / AR / NIAMS NIH HHS / United States R01 AR065402 / AR / NIAMS NIH HHS / United States K01 AR065397 / AR / NIAMS NIH HHS / United States R37 AG013925 / AG / NIA NIH HHS / United States F31 AR067646 / AR / NIAMS NIH HHS / United States R01 AG048388 / AG / NIA NIH HHS / United States T32 AR056950 / AR / NIAMS NIH HHS / United States R01 AR049069 / AR / NIAMS NIH HHS / United States R01 AG013925 / AG / NIA NIH HHS / United States R01 AR068103 / AR / NIAMS NIH HHS / United States |
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