Bone protection by inhibition of microRNA-182

Kazuki Inoue, Zhonghao Deng, Yufan Chen, Eugenia Giannopoulou, Ren Xu, Shiaoching Gong, Matthew B. Greenblatt, Lingegowda S. Mangala, Gabriel Lopez-Berestein, David G. Kirsch, Anil K. Sood, Liang Zhao and Baohong Zhao ()
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Kazuki Inoue: Hospital for Special Surgery
Zhonghao Deng: Hospital for Special Surgery
Yufan Chen: Nanfang Hospital, Southern Medical University
Eugenia Giannopoulou: Hospital for Special Surgery
Ren Xu: Weill Cornell Medical College
Shiaoching Gong: The Rockefeller University
Matthew B. Greenblatt: Weill Cornell Medical College
Lingegowda S. Mangala: The University of Texas MD Anderson Cancer Center
Gabriel Lopez-Berestein: The University of Texas MD Anderson Cancer Center
David G. Kirsch: Duke University Medical Center
Anil K. Sood: The University of Texas MD Anderson Cancer Center
Liang Zhao: Nanfang Hospital, Southern Medical University
Baohong Zhao: Hospital for Special Surgery

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-06446-0

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