Bone protection by inhibition of microRNA-182.

TitleBone protection by inhibition of microRNA-182.
Publication TypeJournal Article
Year of Publication2018
AuthorsInoue K, Deng Z, Chen Y, Giannopoulou E, Xu R, Gong S, Greenblatt MB, Mangala LS, Lopez-Berestein G, Kirsch DG, Sood AK, Zhao L, Zhao B
JournalNat Commun
Date Published2018 10 05
KeywordsAnimals, Arthritis, Rheumatoid, Autocrine Communication, Bone Resorption, eIF-2 Kinase, Female, Homeostasis, Interferon-beta, Male, Mice, Inbred C57BL, Mice, Transgenic, MicroRNAs, Monocytes, Osteogenesis

Targeting microRNAs recently shows significant therapeutic promise; however, such progress is underdeveloped in treatment of skeletal diseases with osteolysis, such as osteoporosis and rheumatoid arthritis (RA). Here, we identified miR-182 as a key osteoclastogenic regulator in bone homeostasis and diseases. Myeloid-specific deletion of miR-182 protects mice against excessive osteoclastogenesis and bone resorption in disease models of ovariectomy-induced osteoporosis and inflammatory arthritis. Pharmacological treatment of these diseases with miR-182 inhibitors completely suppresses pathologic bone erosion. Mechanistically, we identify protein kinase double-stranded RNA-dependent (PKR) as a new and essential miR-182 target that is a novel inhibitor of osteoclastogenesis via regulation of the endogenous interferon (IFN)-β-mediated autocrine feedback loop. The expression levels of miR-182, PKR, and IFN-β are altered in RA and are significantly correlated with the osteoclastogenic capacity of RA monocytes. Our findings reveal a previously unrecognized regulatory network mediated by miR-182-PKR-IFN-β axis in osteoclastogenesis, and highlight the therapeutic implications of miR-182 inhibition in osteoprotection.

Alternate JournalNat Commun
PubMed ID30291236
PubMed Central IDPMC6173760
Grant ListDP5 OD021351 / OD / NIH HHS / United States
R01 AR075585 / AR / NIAMS NIH HHS / United States
R00 AR062047 / AR / NIAMS NIH HHS / United States
R01 AR071463 / AR / NIAMS NIH HHS / United States
R35 CA209904 / CA / NCI NIH HHS / United States
R01 AR068970 / AR / NIAMS NIH HHS / United States
R00 AR062047, R01 AR068970 and R01 AR071463 / / U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) / International