Downregulation of MiR-21 Gene Expression by CRE-Ter to Modulate Osteoclastogenesis: De Novo Mechanism

Overview

Journal Biochem Biophys Rep

Specialty Biochemistry

Date 2021 May 17

PMID 33997317

Citations 2

Authors

Yutthana Pengjam

Thanet Prajantasen

Natda Tonwong

Pharkphoom Panichayupakaranant

Affiliations

Soon will be listed here.

Abstract

miR-21 expression stimulates osteoclast cells in the context of osteoclastogenesis. A previous report showed that NFκB-miR-21 pathway could serve as an innovative alternative to devise therapeutics for healing diabetic ulcers. Furthermore, our study demonstrated that a highly water-soluble curcuminoids-rich extract (CRE-Ter) inhibits osteoclastogenesis through NFκB pathway. The interplay between miR-21 and CRE-Ter in osteoclastogenesis has not yet been investigated. In this study, we examined the relation of CRE-Ter and miR-21 gene expression in receptor of the nuclear factor κB (NFκB) ligand (RANKL) - induced murine monocyte/macrophage RAW 264.7 cells, osteoclast cells, in osteoclastogenesis. Effect of CRE-Ter on generation of intracellular reactive oxygen species (ROS) was estimated by dichlorofluorescein diacetate (DCFH-DA). The results reveal that CRE-Ter reduced expression levels of miR-21 gene in osteoclasts. The inhibitory effects of CRE-Ter on osteoclastogenesis were evaluated by reduction in tartrate-resistant acid phosphatase (TRAP) content, and by reduction in expression levels of an osteoclast-specific gene, cathepsin K. Treatment of the osteoclast cells with CRE-Ter suppressed RANKL-induced NFκB activation including phospho-NFκB-p65, and phospho IκBα proteins. Western blot analysis revealed that NFκB inhibitor up-regulated CRE-Ter-promoted expression of phospho-NFκB-p65. In addition, CRE-Ter dose-dependently inhibited phospho-Akt expression. CRE-Ter also dose-dependently reduced DNA binding activity of NFκB and Akt as revealed by EMSA. ChIP assay revealed binding of NFκB-p65 to miR-21 promoters. In conclusion, our results demonstrate that CRE-Ter downregulates miR-21 gene expression in osteoclasts via a de novo mechanism, NFκB- Akt-miR-21 pathway.

Citing Articles

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Modified Curcuminoid-Rich Extract Liposomal CRE-SDInhibits Osteoclastogenesis via the Canonical NF-κB Signaling Pathway.

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References

Darnay B, Haridas V, Ni J, Moore P, Aggarwal B . Characterization of the intracellular domain of receptor activator of NF-kappaB (RANK). Interaction with tumor necrosis factor receptor-associated factors and activation of NF-kappab and c-Jun N-terminal kinase. J Biol Chem. 1998; 273(32):20551-5. DOI: 10.1074/jbc.273.32.20551. View

Gamez B, Rodriguez-Carballo E, Ventura F . MicroRNAs and post-transcriptional regulation of skeletal development. J Mol Endocrinol. 2014; 52(3):R179-97. DOI: 10.1530/JME-13-0294. View

Xie L, Li X, Takahara S . Curcumin has bright prospects for the treatment of multiple sclerosis. Int Immunopharmacol. 2010; 11(3):323-30. DOI: 10.1016/j.intimp.2010.08.013. View

Li Y, Jiang Z, Chen H, Ma W . A modified quantitative EMSA and its application in the study of RNA--protein interactions. J Biochem Biophys Methods. 2004; 60(2):85-96. DOI: 10.1016/j.jbbm.2004.03.008. View

Ammon H, Wahl M . Pharmacology of Curcuma longa. Planta Med. 1991; 57(1):1-7. DOI: 10.1055/s-2006-960004. View

Kumarswamy R, Volkmann I, Thum T . Regulation and function of miRNA-21 in health and disease. RNA Biol. 2011; 8(5):706-13. PMC: 3256347. DOI: 10.4161/rna.8.5.16154. View

Woo J, Kim Y, Choi Y, Kim D, Lee K, Bae J . Molecular mechanisms of curcumin-induced cytotoxicity: induction of apoptosis through generation of reactive oxygen species, down-regulation of Bcl-XL and IAP, the release of cytochrome c and inhibition of Akt. Carcinogenesis. 2003; 24(7):1199-208. DOI: 10.1093/carcin/bgg082. View

Lee S, Woo K, Kim S, Kim H, Kwack K, Lee Z . The phosphatidylinositol 3-kinase, p38, and extracellular signal-regulated kinase pathways are involved in osteoclast differentiation. Bone. 2002; 30(1):71-7. DOI: 10.1016/s8756-3282(01)00657-3. View

Aggarwal B, Shishodia S, Takada Y, Banerjee S, Newman R, Bueso-Ramos C . Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB pathway in breast cancer cells and inhibits lung metastasis of human breast cancer in nude mice. Clin Cancer Res. 2005; 11(20):7490-8. DOI: 10.1158/1078-0432.CCR-05-1192. View

10.

Boyle W, Simonet W, Lacey D . Osteoclast differentiation and activation. Nature. 2003; 423(6937):337-42. DOI: 10.1038/nature01658. View

11.

Suda T, Udagawa N, Nakamura I, Miyaura C, Takahashi N . Modulation of osteoclast differentiation by local factors. Bone. 1995; 17(2 Suppl):87S-91S. DOI: 10.1016/8756-3282(95)00185-g. View

12.

Anand P, Sundaram C, Jhurani S, Kunnumakkara A, Aggarwal B . Curcumin and cancer: an "old-age" disease with an "age-old" solution. Cancer Lett. 2008; 267(1):133-64. DOI: 10.1016/j.canlet.2008.03.025. View

13.

Zhou R, Hu G, Gong A, Chen X . Binding of NF-kappaB p65 subunit to the promoter elements is involved in LPS-induced transactivation of miRNA genes in human biliary epithelial cells. Nucleic Acids Res. 2010; 38(10):3222-32. PMC: 2879527. DOI: 10.1093/nar/gkq056. View

14.

Ribas J, Lupold S . The transcriptional regulation of miR-21, its multiple transcripts, and their implication in prostate cancer. Cell Cycle. 2010; 9(5):923-9. PMC: 3462654. DOI: 10.4161/cc.9.5.10930. View

15.

Anand P, Thomas S, Kunnumakkara A, Sundaram C, Harikumar K, Sung B . Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature. Biochem Pharmacol. 2008; 76(11):1590-611. DOI: 10.1016/j.bcp.2008.08.008. View

16.

Moon H, Ko W, Han S, Kim D, Hwang Y, Park H . Antioxidants, like coenzyme Q10, selenite, and curcumin, inhibited osteoclast differentiation by suppressing reactive oxygen species generation. Biochem Biophys Res Commun. 2012; 418(2):247-53. DOI: 10.1016/j.bbrc.2012.01.005. View

17.

Nelson K, Dahlin J, Bisson J, Graham J, Pauli G, Walters M . The Essential Medicinal Chemistry of Curcumin. J Med Chem. 2017; 60(5):1620-1637. PMC: 5346970. DOI: 10.1021/acs.jmedchem.6b00975. View

18.

Weisberg S, Leibel R, Tortoriello D . Dietary curcumin significantly improves obesity-associated inflammation and diabetes in mouse models of diabesity. Endocrinology. 2008; 149(7):3549-58. PMC: 2453081. DOI: 10.1210/en.2008-0262. View

19.

Madhyastha R, Madhyastha H, Pengjam Y, Nakajima Y, Omura S, Maruyama M . NFkappaB activation is essential for miR-21 induction by TGFβ1 in high glucose conditions. Biochem Biophys Res Commun. 2014; 451(4):615-21. DOI: 10.1016/j.bbrc.2014.08.035. View

20.

Roy S, Khanna S, Hussain S, Biswas S, Azad A, Rink C . MicroRNA expression in response to murine myocardial infarction: miR-21 regulates fibroblast metalloprotease-2 via phosphatase and tensin homologue. Cardiovasc Res. 2009; 82(1):21-9. PMC: 2652741. DOI: 10.1093/cvr/cvp015. View