Deficiency of DGCR8 increases bone formation through downregulation of miR-22 expression

Abstract

MicroRNAs (miRNA) significantly contribute to bone formation by post-transcriptional regulation of gene expression. Mature miRNAs are generated following sequential cleavage by DROSHA/DGCR8 and DICER. However, recent studies have identified that some miRNAs require only one of these enzymes. Most studies seeking to clarify the role of miRNA during bone formation have been performed using DICER deletion strategies, but little is known regarding the role of DGCR8. To study the function of DGCR8 in osteogenesis, we generated mice in which Dgcr8 is conditionally deleted in osteoprogenitor cells by Col1a1-Cre. Dgcr8-cKO mice showed increased bone volume (BV/TV), trabecular number (Tb/N), and trabecular thickness (Tb.Th), but decreased trabecular separation (Tb.Sp) in the femur. Von Kossa, tartrate-resistant acid phosphatase staining, and calcein double labeling identified that osteoblast activity is increased in Dgcr8-cKO mice. In an effort to elucidate a detailed cellular mechanism, we found that miR-22 was downregulated in Dgcr8-cKO mice, leading to upregulation of the osteocalcin transcript, a key marker of osteoblasts. Interestingly, the mRNA expression level of Dgcr8 was decreased during osteoblast differentiation. Taken together, these results strongly indicate that DGCR8-dependent generation of miR-22 is essential for bone formation and that miR-22 could be a therapeutic target for individuals with bone disease.