کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5509360 1538510 2017 11 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Inhibition of PRMT5 suppresses osteoclast differentiation and partially protects against ovariectomy-induced bone loss through downregulation of CXCL10 and RSAD2
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی زیست شیمی
پیش نمایش صفحه اول مقاله
Inhibition of PRMT5 suppresses osteoclast differentiation and partially protects against ovariectomy-induced bone loss through downregulation of CXCL10 and RSAD2
چکیده انگلیسی


- Inhibition of PRMT5 suppresses RANKL-induced osteoclast differentiation.
- Administration of PRMT5 inhibitor (EPZ015666) attenuates ovariectomy-induced bone loss in mice.
- Inhibition of PRMT5 suppresses RANKL-induced NF-κB and MAPK activation as well as osteoclast related marker genes.
- CXCL10 and RSAD2 are involved in EPZ-mediated osteoclastogenesis inhibition.
- PRMT5 knockdown or inhibition results in reduction in H3R8me2s/H4R3me2s occupancy at the CXCL10 and RSAD2 promoters.

Protein arginine methyltransferase 5 (PRMT5) is an arginine methylation methyltransferase that regulates various physiological processes. Abnormal PRMT5 activity has been reported in inflammation and various types of cancers. Because osteoclast differentiation is characterized by the activation of inflammation-related pathways, we speculated that PRMT5 may play a role in this process. In the present study, we found that PRMT5 was upregulated during osteoclast differentiation. Knockdown of PRMT5 with siRNA in bone marrow mononuclear cells (BMMs) resulted in inhibition of receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation. Consistent with the PRMT5 knockdown results, the PRMT5 inhibitor EPZ015666 (EPZ) suppressed osteoclast differentiation and bone resorption. Intraperitoneal administration of EPZ prevented ovariectomy-induced bone loss. Moreover, RANKL-induced NF-κB and MAPK activation was inhibited by EPZ. Expression microarrays showed that the expression of several osteoclast formation-related genes was altered by EPZ treatment, including chemokine C-X-C motif ligand 10 (CXCL10). Administration of recombinant CXCL10 partially reversed the osteoclastogenesis inhibition effect of the PRMT5 inhibitor. Intriguingly, RSAD2, which is a reported antiviral protein, was apparently suppressed when PRMT5 was inhibited. Knockdown of RSAD2 with siRNA in BMMs led to inhibition of osteoclast differentiation. Subsequent ChIP-qPCR identified that both PRMT5 inhibition and knockdown resulted in decreased H3R8 or/and H4R3 methylation at CXCL10 and RSAD2 promotors. In conclusion, our study found that PRMT5 is an activator of osteoclast differentiation and inhibition of PRMT5 partially suppressed osteoclastogenesis through downregulation of CXCL10 and RSAD2.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Cellular Signalling - Volume 34, June 2017, Pages 55-65
نویسندگان
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