Authors: Sugatani T, Vacher J, Hruska KA.
MicroRNAs (miRs) are small non-coding RNAs that principally function in the spatiotemporal regulation of protein translation in animal cells. Though emerging evidence suggests that some miRs play important roles in osteoblastogenesis and skeletal homeostasis, much less is known in osteoclastogenesis. Here we show that receptor activator of NFκB ligand (RANKL)-induced osteoclastogenesis is mediated by miR-21. MiR-21 was identified as a miR expression signature of RANKL-induced osteoclastogenesis that downregulates programmed cell death 4 (PDCD4) protein levels. Diminished PDCD4 removes a repression from c-Fos, a critical transcription factor for osteoclastogenesis and osteoclast-specific downstream target genes. In addition, RANKL-induced c-Fos up-regulates miR-21 gene expression. Bone marrow-derived monocyte/macrophage precursors deficient of DGCR8, an RNA binding protein associated with miR biogenesis, and Dicer, an endoribonuclease in the RNase ΙΙΙ family associated with miR biogenesis, possessed significantly decreased miR-21 levels and increased PDCD4 protein levels so that RANKL-induced osteoclastogenesis was impaired in those cells. However, forced expression of miR-21 rescued osteoclast development due to downregulation of PDCD4 protein expression levels. Thus, our studies provide a new molecular mechanism including a positive feedback loop of c-Fos/miR-21/PDCD4 regulating osteoclastogenesis.Full Text