Bone has several crucial functions including mechanical support of movement, hematopoiesis, maintenance of mineral homeostasis, and energy regulation. Bone also undergoes continuous remodeling to maintain its structural integrity, which suggests it has strong respiration and energy consumption capability. It has been shown that during development, bones, in particular, osteoblasts, rely on glucose uptake for proper skeletal development. However, the effect of energy utilization on osteocytes’ function is currently unknown. Osteocytes are terminally differentiated osteoblasts and are deeply embedded into the mineralized matrix of bone. Previous studies have shown that PTH promotes bone anabolism, in part, by stimulating osteoblasts anaerobic glycolysis while suppressing glucose oxidation through the TCA cycle. In osteocytes, PTH suppresses Sost expression (the gene encoding a potent inhibitor of bone formation) by inducing HDAC4/5 nuclear translocation and MEF2C inhibition. Recently, Scriptaid, an HDAC complex inhibitor, has been shown to induce Mef2 expression and exercise-like adaptation in mouse muscles. In myocytes, Scriptaid disrupts the HDACs co-repressor complex and induces nuclear export of HDAC4/5 with MEF2 activation. This will subsequently increase the expressions of several genes related to energy utilization such as Glut4 and Pdk4. Thus we hypothesized that Scriptaid might regulate Sost and Glut4 expression in osteocytes.
To investigate the effect of Scriptaid on osteocytes, we treated a mouse osteocytic cell line, Ocy454-12H, with Scriptaid. Unexpectedly, Scriptaid potently suppressed Sost, whereas it increased Glut4 expression. Scriptaid stimulated osteocyte respiration and glucose consumption rate. Mechanistically, Scriptaid treatment of Ocy454-12H induced nuclear translocation of Hdac5 whereas it did not affect Hdac4. Silencing of Hdac5 expression with shRNA increased Sost basal expression and blocked Sost suppression induced by Scriptaid. However, Glut4 up-regulation by Scriptaid was independent of the HDAC4/5-MEF2C pathway. Glut4 luciferase reporter assays demonstrated that two additional transcription factors binding sites, O/E&NF1 and C/EBPα, may mediate Scriptaid-induced Glut4 up-regulation. Taken together, these data demonstrate that in osteocytes Scriptaid suppresses Sost expression through regulating HDAC5-MEF2C signaling. However, Scriptaid increases Glut4 expression through Hdac5-independent mechanisms, and dependent on O/E&NF1 and C/EBPα.
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