Hdac3 deficiency limits periosteal reaction associated with Western diet feeding in female mice

TL;DR

Deleting Hdac3 improves bone healing in obese female mice, possibly by increasing CCL2 production.

Contribution

This study shows that Hdac3 deficiency enhances bone healing in diet-induced obesity through CCL2.

Findings

Hdac3 ablation increased bone volume and reduced periosteal reaction in HFD-fed female mice.

Osteoblasts in Hdac3-ablated conditioned medium showed higher mineralization and osteogenic gene expression.

Hdac3 deficiency elevated CCL2 secretion and increased CCL2-positive cells in bone defects.

Abstract

Diet‐induced obesity is associated with enhanced systemic inflammation that limits bone regeneration. HDAC inhibitors are currently being explored as anti‐inflammatory agents. Prior reports show that myeloid progenitor‐directed Hdac3 ablation enhances intramembranous bone healing in female mice. In this study, we determined if Hdac3 ablation increased intramembranous bone regeneration in mice fed a high‐fat/high‐sugar (HFD) diet. Micro‐CT analyses demonstrated that HFD‐feeding enhanced the formation of periosteal reaction tissue of control littermates, reflective of suboptimal bone healing. We confirmed enhanced bone volume within the defect of Hdac3‐ablated females and showed that Hdac3 ablation reduced the amount of periosteal reaction tissue following HFD feeding. Osteoblasts cultured in a conditioned medium derived from Hdac3‐ablated cells exhibited a four‐fold increase in mineralization and enhanced osteogenic gene expression. We found that Hdac3 ablation elevated the secretion of several chemokines, including CCL2. We then confirmed that Hdac3 deficiency increased the expression of Ccl2. Lastly, we show that the proportion of CCL2‐positve cells within bone defects was significantly higher in Hdac3‐deficient mice and was further enhanced by HFD. Overall, our studies demonstrate that Hdac3 deletion enhances intramembranous bone healing in a setting of diet‐induced obesity, possibly through increased production of CCL2 by macrophages within the defect.

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