Bone protection by inhibition of microRNA-182

被引：86

作者：

Inoue, Kazuki ^{[1
,2
]}

Deng, Zhonghao ^{[1
]}

Chen, Yufan ^{[3
]}

Giannopoulou, Eugenia ^{[1
,4
]}

Xu, Ren ^{[5
]}

Gong, Shiaoching ^{[6
]}

Greenblatt, Matthew B. ^{[5
]}

Mangala, Lingegowda S. ^{[7
,8
]}

Lopez-Berestein, Gabriel ^{[8
,9
]}

Kirsch, David G. ^{[10
]}

Sood, Anil K. ^{[7
,8
,11
]}

Zhao, Liang ^{[3
]}

Zhao, Baohong ^{[1
,2
,12
]}

机构：

[1] Hosp Special Surg, David Z Rosensweig Genom Res Ctr, Arthrit & Tissue Degenerat Program, New York, NY 10021 USA

[2] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA

[3] Southern Med Univ, Nanfang Hosp, Dept Orthoped Surg, Guangzhou 510515, Guangdong, Peoples R China

[4] CUNY, New York City Coll Technol, Biol Sci Dept, Brooklyn, NY 11201 USA

[5] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY 10065 USA

[6] Rockefeller Univ, Dept Mol Biol, New York, NY 10065 USA

[7] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol & Reprod Med, Houston, TX 77030 USA

[8] Univ Texas MD Anderson Canc Ctr, Ctr RNA Interference & Noncoding RNA, Houston, TX 77030 USA

[9] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA

[10] Duke Univ, Dept Radiat Oncol & Dept Pharmacol & Canc Biol, Med Ctr, Durham, NC 27710 USA

[11] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA

[12] Weill Cornell Grad Sch Med Sci, Grad Program Biochem Cell & Mol Biol, New York, NY 10065 USA

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

中国国家自然科学基金; 美国国家卫生研究院;

关键词：

PROTEIN-KINASE PKR; RHEUMATOID-ARTHRITIS; INTERFERON-BETA; THERAPEUTIC TARGETS; RBP-J; INDUCED OSTEOCLASTOGENESIS; TRANSCRIPTION FACTOR; RNA-SEQ; DIFFERENTIATION; MIR-182;

D O I：

10.1038/s41467-018-06446-0

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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)-beta-mediated autocrine feedback loop. The expression levels of miR-182, PKR, and IFN-beta 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-beta axis in osteoclastogenesis, and highlight the therapeutic implications of miR-182 inhibition in osteoprotection.

引用

页数：17

共 70 条

[1]

Characterization of transgenic mice with targeted disruption of the catalytic domain of the double-stranded RNA-dependent protein kinase, PKR [J].