TY - JOUR
T1 - Bone protection by inhibition of microRNA-182
AU - Inoue, Kazuki
AU - Deng, Zhonghao
AU - Chen, Yufan
AU - Giannopoulou, Eugenia
AU - Xu, Ren
AU - Gong, Shiaoching
AU - Greenblatt, Matthew B.
AU - Mangala, Lingegowda S.
AU - Lopez-Berestein, Gabriel
AU - Kirsch, David G.
AU - Sood, Anil K.
AU - Zhao, Liang
AU - Zhao, Baohong
N1 - Funding Information:
We thank Drs. Gökhan Hotamisligil, Carl Nathan and Xiuju Jiang for providing Pkr−/− mice and their control mice, Dr. Giancarlo Chesi and David Kuo for technical assistance, and Dr. Steven R. Goldring for discussions. We are grateful to Christine Miller, Mahmoud Elguindy, Gregory Vitone, Shin-ichi Nakano, and Cheng Xu from Dr. Bao-hong Zhao’s laboratory for their helpful discussions and assistance. We thank Weill Cornell Genomics Resources Core Facility for their efficient and high quality sequencing service and related analysis. A.K.S. is supported by American Cancer Society Research Professor Award and NIH R35 CA209904, and L.Z. is supported by National Natural Science Foundation of China (31771051). This work was supported by grants from the National Institutes of Health (R00 AR062047, R01 AR068970, and R01 AR071463 to B. Z.). The content of this manuscript is solely the responsibilities of the authors and does not necessarily represent the official views of the NIH.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-06446-0
DO - 10.1038/s41467-018-06446-0
M3 - Article
C2 - 30291236
AN - SCOPUS:85054449932
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4108
ER -