Hdac3 regulates bone modeling by suppressing osteoclast responsiveness to RANKL.

Hdac3 is a lysine deacetylase that removes acetyl groups from histones and additional proteins. While Hdac3 functions within mesenchymal lineage skeletal cells are defined, little is known Hdac3 activities in bone resorbing osteoclasts.  In this study we conditionally deleted Hdac3 within Ctsk-expressing cells and examined the effects on bone modeling and osteoclast differentiation in mice. Hdac3 deficiency reduced femur and tibia periosteal circumference and increased cortical periosteal osteoclast number. Trabecular bone was likewise reduced and was accompanied by increased osteoclast number per trabecular bone surface. We previously showed that Hdac3 deacetylates the p65 subunit of the NFκB transcriptional complex to decrease DNA binding and transcriptional activity. Hdac3 deficient osteoclasts demonstrate increased K310 NFκB acetylation and NFκB transcriptional activity. Hdac3 deficient osteoclast lineage cells were hyper-responsive to RANKL and showed elevated ex vivo osteoclast number and size and enhanced bone resorption in pit formation assays. Osteoclast-directed Hdac3 deficiency decreased cortical and trabecular bone mass parameters, suggesting that Hdac3 regulates coupling of bone resorption and bone formation. We surveyed a panel of osteoclast-derived coupling factors and found that Hdac3 suppression diminished S1P production. Osteoclast-derived S1P acts in paracrine to promote bone mineralization. Mineralization of wild type bone marrow stromal cells cultured with conditioned medium from Hdac3 deficient osteoclasts was markedly reduced.  Expression of Alkaline phosphatase, Type Collagen 1a1 and Osteocalcin was also suppressed, but no change in Runx2 expression was observed. Our results demonstrate that Hdac3 controls bone modeling by suppressing osteoclast lineage cell responsiveness to RANKL and coupling to bone formation. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.