MiR-7b directly targets DC-STAMP causing suppression of NFATc1 and c-Fos signaling during osteoclast fusion and differentiation.

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  • Additional Information
    • Source:
      Publisher: Elsevier Pub. Co Country of Publication: Netherlands NLM ID: 0217513 Publication Model: Print-Electronic Cited Medium: Print ISSN: 0006-3002 (Print) Linking ISSN: 00063002 NLM ISO Abbreviation: Biochim Biophys Acta Subsets: MEDLINE
    • Publication Information:
      Original Publication: Amsterdam : Elsevier Pub. Co.
    • Subject Terms:
      Genes, fos*/genetics; Cell Differentiation/*genetics ; Membrane Proteins/*genetics ; MicroRNAs/*physiology ; NFATC Transcription Factors/*genetics ; Nerve Tissue Proteins/*genetics ; Osteoclasts/*physiology; Animals ; Cell Fusion ; Cells, Cultured ; Down-Regulation/genetics ; HEK293 Cells ; Humans ; Mice ; Mice, Inbred C57BL ; NFATC Transcription Factors/metabolism ; RNA Interference/physiology ; Signal Transduction/genetics
    • Abstract:
      DC-STAMP is a key regulating molecule of osteoclastogenesis and osteoclast precursor (OCP) fusion. Emerging lines of evidence showed that microRNAs play crucial roles in bone metabolism and osteoclast differentiation, but no microRNA has yet been reported to be directly related to OCPs fusion. Through a microarray, we found that the expression of miR-7b in RAW264.7 cells was significantly decreased after induction with M-CSF and RANKL. The overexpression of miR-7b in RAW264.7 cells attenuated the number of TRAP-positive cells number and the formation of multinucleated cells, whereas the inhibition of miR-7b enhanced osteoclastogenesis. Through a dual luciferase reporter assay, we confirmed that miR-7b directly targets DC-STAMP. Other fusogenic molecules, such as CD47, ATP6v0d2, and OC-STAMP, were detected to be down-regulated in accordance with the inhibition of DC-STAMP. Because DC-STAMP also participates in osteoclast differentiation through the ITAM-ITIM network, multiple osteoclast-specific genes in the ITAM-ITIM network were detected to identify how DC-STAMP is involved in this process. The results showed that molecules associated with the ITAM-ITIM network, such as NFATc1 and OSCAR, which are crucial in osteoclastogenesis, were consistently altered due to DC-STAMP inhibition. These findings suggest that miR-7b inhibits osteoclastogenesis and cell-cell fusion by directly targeting DC-STAMP. In addition, the inhibition of DC-STAMP and its downstream signals changed the expression of other fusogenic genes and key regulating genes, such as Nfatc1, c-fos, Akt, Irf8, Mapk1, and Traf6. In conclusion, our findings indicate that miR-7b may be a potential therapeutic target for the treatment of osteoclast-related bone disorders.
      (Copyright © 2014 Elsevier B.V. All rights reserved.)
    • Contributed Indexing:
      Keywords: Cell fusion; DC-STAMP; Osteoclastogenesis; microRNA
    • Accession Number:
      0 (DC-STAMP protein, mouse)
      0 (MIRN7 microRNA, mouse)
      0 (Membrane Proteins)
      0 (MicroRNAs)
      0 (NFATC Transcription Factors)
      0 (Nerve Tissue Proteins)
      0 (Nfatc1 protein, mouse)
    • Publication Date:
      Date Created: 20140816 Date Completed: 20150113 Latest Revision: 20220331
    • Publication Date:
      20240829
    • Accession Number:
      10.1016/j.bbagrm.2014.08.002
    • Accession Number:
      25123438