Abstract
Hdac3 is a lysine deacetylase that removes acetyl groups from histones and additional proteins. Although Hdac3 functions within mesenchymal lineage skeletal cells are defined, little is known about 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 NF-κB transcriptional complex to decrease DNA-binding and transcriptional activity. Hdac3-deficient osteoclasts demonstrate increased K310 NF-κB acetylation and NF-κB 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 sphingosine-1-phosphate production. Osteoclast-derived sphingosine-1-phosphate acts in paracrine to promote bone mineralization. Mineralization of WT bone marrow stromal cells cultured with conditioned medium from Hdac3-deficient osteoclasts was markedly reduced. Expression of alkaline phosphatase, type 1a1 collagen, 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.
Highlights
Skeletal element width varies with sex, age, ethnicity, and geography [1,2,3,4], and can predict fracture risk independent of bone mass
Together these data suggest that Hdac3 deletion in Ctsk-expressing cells decreases skeletal element width by enhancing NF-kB transcriptional activity, osteoclast numbers, and bone resorption and that Sphk1 reduction facilitates this uncoupled bone loss
We show that deletion of Hdac3 in Ctsk-expressing cells diminishes periosteal bone diameter and limits acquisition of trabecular bone mass
Summary
Skeletal element width (e.g. periosteal circumference) varies with sex, age, ethnicity, and geography [1,2,3,4], and can predict fracture risk independent of bone mass. We show that deletion of Hdac within Ctsk-expressing cells alters bone modeling by decreasing skeletal element width (e.g. periosteal circumference without a change in bone length). This coincides with increased numbers of periosteal osteoclasts. Likewise, conditioned medium generated from Hdac3-deficient osteoclasts does not support osteoblast-mediated matrix mineralization Together these data suggest that Hdac deletion in Ctsk-expressing cells decreases skeletal element width by enhancing NF-kB transcriptional activity, osteoclast numbers, and bone resorption and that Sphk reduction facilitates this uncoupled bone loss
Published Version (Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have