Abstract
Mechanical stimulation and histone deacetylases (HDACs) have essential roles in regulating the osteogenic differentiation of bone marrow stromal cells (BMSCs) and bone formation. However, little is known regarding what regulates HDAC expression and therefore the osteogenic differentiation of BMSCs during osteogenesis. In this study, we investigated whether mechanical loading regulates HDAC expression directly and examined the role of HDACs in mechanical loading-triggered osteogenic differentiation and bone formation. We first studied the microarrays of samples from patients with osteoporosis and found that the NOTCH pathway and skeletal development gene sets were downregulated in the BMSCs of patients with osteoporosis. Then we demonstrated that mechanical stimuli can regulate osteogenesis and bone formation both in vivo and in vitro. NOTCH signaling was upregulated during cyclic mechanical stretch (CMS)-induced osteogenic differentiation, whereas HDAC1 protein expression was downregulated. The perturbation of HDAC1 expression also had a significant effect on matrix mineralization and JAG1-mediated Notch signaling, suggesting that HDAC1 acts as an endogenous attenuator of Notch signaling in the mechanotransduction of BMSCs. Chromatin immunoprecipitation (ChIP) assay results suggest that HDAC1 modulates the CMS-induced histone H3 acetylation level at the JAG1 promoter. More importantly, we found an inhibitory role of Hdac1 in regulating bone formation in response to hindlimb unloading in mice, and pretreatment with an HDAC1 inhibitor partly rescued the osteoporosis caused by mechanical unloading. Our results demonstrate, for the first time, that mechanical stimulation orchestrates genes expression involved in the osteogenic differentiation of BMSCs via the direct regulation of HDAC1, and the therapeutic inhibition of HDAC1 may be an efficient strategy for enhancing bone formation under mechanical stimulation.
Highlights
Enhances the activity of alkaline phosphatase (ALP) and the rate calcium deposition.[9]
We found that HDAC1 was negatively correlated with osteogenic differentiation and bone formation in the bone marrow stromal cells (BMSCs) of patients with osteoporosis, whereas jagged 1 (JAG1)-mediated NOTCH signaling was upregulated
Mechanical loading directly induced a downregulation of HDAC1 expression, which was involved in the promotion of osteogenic differentiation and bone formation through the targeting of JAG1, a master inducer of osteogenic differentiation.[21,22,23]
Summary
Enhances the activity of alkaline phosphatase (ALP) and the rate calcium deposition.[9]. Total HDAC enzymatic activity is decreased, with a significant reduction in HDAC1 expression Consistent with this finding, the recruitment of HDAC1 to the promoters of osteoblast marker genes, including osterix (Osx) and osteocalcin (Ocn), is downregulated, whereas histone H3 and H4 are hyperacetylated at those promoters during osteogenic differentiation.[19] Previous studies have shown that the suppression of HDAC activity with HDAC inhibitors accelerates osteogenesis.[20] little is known regarding what regulates HDAC expression during osteogenesis. Mechanical loading directly induced a downregulation of HDAC1 expression, which was involved in the promotion of osteogenic differentiation and bone formation through the targeting of JAG1, a master inducer of osteogenic differentiation.[21,22,23] Our findings demonstrate that the therapeutic inhibition of HDAC1 may partly rescue osteoporosis caused by mechanical unloading. This study may provide a novel mechanism and potential therapeutic target for enhancing bone formation under mechanical stimulation
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