title: A microRNA expression signature of osteoclastogenesis.
abstract: MicroRNAs (miRs) are small noncoding RNAs that principally function in the spatiotemporal regulation of protein translation in animal cells. Although 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 nuclear factor κB ligand (RANKL)-induced osteoclastogenesis is mediated by miR-21. MiR-21 was identified as an miR expression signature of RANKL-induced osteoclastogenesis that down-regulates 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 DiGeorge syndrome critical region gene 8, an RNA binding protein associated with miR biogenesis, and Dicer, an endoribonuclease in the RNaseIII 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 because of down-regulation 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.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Avenue, St Louis, MO 63110, USA. sugatani_t@kids.wustl.edu
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Sugatani
authors.forename: Jean
authors.initials: J
authors.lastname: Vacher
authors.forename: Keith A
authors.initials: KA
authors.lastname: Hruska
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D053245:RANK Ligand / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000235:genetics; D043244:Ribonuclease III / Q000235:genetics; D014162:Transfection
chemical_list: D051017:Apoptosis Regulatory Proteins; D035683:MicroRNAs; C498443:Pdcd4 protein, mouse; D053245:RANK Ligand; D016601:RNA-Binding Proteins; D043244:Ribonuclease III