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

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Science Signaling  09 Aug 2016:
Vol. 9, Issue 440, pp. ra79
DOI: 10.1126/scisignal.aaf3273

Growing bones need histone deacetylase

Histone deacetylase (HDAC) inhibitors may be therapeutic in various diseases, but their use causes birth defects and is detrimental to growing bones or the repair of injured bones. Cartilage provides the bone-promoting matrix and bone-forming progenitor cells required for the formation of long bones. Carpio et al. found that HDAC3 promotes pre- and postnatal bone growth by restricting the secretion of inflammatory factors from cartilage cells called chondrocytes. Mice lacking chondrocyte-specific Hdac3 died in utero, and inducible transgenic mice lacking postnatal HDAC3 in chondrocytes had impaired long bone development. Chondrocytes from these mice had increased acetylation of a proinflammatory transcription factor as well as of histones in and near loci encoding secreted proinflammatory factors that promote matrix degradation and the proliferation and activity of bone-resorbing osteoclasts. The findings explain why HDAC inhibitors cause skeletal defects and are ill-advised for children and pregnant women as well as for patients with bone fractures.


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.

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