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) meth-yltransferase Setdb1, which was sensitive to mechanical unloading, was increased during osteogenic differen-tiation 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.

Automated summary

Emerging evidence suggests that multiple mechanisms are involved in bone loss induced by mechanical unloading. A new study shows that histone modification plays a crucial role in osteogenic differentiation under mechanical unloading. The study demonstrated that Setdb1, a histone methyltransferase, is increased during osteogenic differentiation and its knockdown blocks osteoblast function. Further investigation revealed that Setdb1 inhibits the expression of miR-212-3p, which suppresses osteogenic differentiation by downregulating Hmgb1 expression. These findings highlight the potential of the Setdb1/miR-212-3p/Hmgb1 pathway as a protective strategy against bone loss induced by mechanical unloading.