Histone methyltransferase Setdb1 mediates osteogenic differentiation by suppressing the expression of miR-212-3p under mechanical unloading

Emerging evidence indicates that multiple mechanisms are involved in bone loss induced by mechanical unloading. Thus far, few study has established the pathophysiological role of histone modification for osteogenic differentiation under mechanical unloading. Here we demonstrated that the histone H3 lysine 9 (H3K9) methyltransferase Setdb1, which was sensitive to mechanical unloading, was increased during osteogenic differentiation of MC3T3-E1 cells for the first time. Knockdown of Setdb1 significantly blocked osteoblast function in vivo and in vitro. Through bioinformatics analysis of candidate miRNAs regulated by H3K9me3, we further identified that Setdb1 inhibited the expression of miR-212-3p by regulating the formation of H3K9me3 in the promoter region. Mechanically, we revealed that miR-212-3p was upregulated under mechanical unloading and suppressed osteogenic differentiation by directly downregulating High mobility group box 1 protein (Hmgb1) expression. Furthermore, we verified the molecular mechanism of the SETDB1/miR-212-3p/HMGB1 pathway in hFOB cells under mechanical unloading. In summary, these data demonstrate the essential function of the Setdb1/miR-212-3p/Hmgb1 pathway in osteogenic differentiation under mechanical unloading, and present a potential protective strategies against bone loss induced by mechanical unloading. •The reduction in bone loading results in disuse bone loss.•Setdb1 is sensitive to unloading and upregulated during osteogenic differentiation.•Setdb1 inhibits miR-212-3p expression by mediating H3K9me3 in the promoter region.•Hmgb1 is a direct target of miR-212-3p and promotes osteogenic differentiation.•The Setdb1/miR-212-3p/Hmgb1 axis regulates osteogenic differentiation in unloading.