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Strontium inhibits osteoclastogenesis by enhancing LRP6 and β-catenin-mediated OPG targeted by miR-181d-5p

  • Tianhao Sun
  • Zhaoyang Li
  • Xing Zhong
  • Zhe Cai
  • Ziyu Ning
  • Tianheng Hou
  • Lifeng Xiong
  • Yu FengEmail author
  • Frankie LeungEmail author
  • William W. LuEmail author
  • Songlin PengEmail author
Research Article

Abstract

Strontium is a drug with the bone formation and anti-resorption effects on bone. The underlying mechanisms for the dual effect of strontium on bone metabolism, especially for the anti-resorption effects remain unknown. Thus, we aim to investigate the mechanisms of effects of strontium on osteoclastogenesis. Firstly, we found that strontium decreased the levels of important biomarkers of receptor activator of nuclear factor kappa-B ligand (RANKL) which induced osteoclast differentiation, indicating that strontium might directly inhibit osteoclast differentiation. Next, we revealed that strontium enhanced Low Density Lipoprotein Receptor-Related Protein 6 (LRP6)/β-catenin/osteoprotegerin (OPG) signaling pathway in MC3T3-E1 cells. The signaling pathway may negatively regulate osteoclastogenesis. Thus, strontium indirectly inhibited RANKL induced osteoclast differentiation. Finally, we revealed that OPG was targeted by miR-181d-5p as determined by luciferase reporter assay and downregulated by miR-181d-5p at both mRNA and protein levels as determined by western blot.

Keywords

Strontium Osteoclast MiR-181 Osteoprotegerin β-catenin 

Abbreviations

RANKL

nuclear factor kappa-B ligand

LRP6

Low Density Lipoprotein Receptor-Related Protein 6

OPG

osteoprotegerin

RBPJ

Recombining binding protein suppressor of hairless

HES

hairy and enhancer of split

HEY

hairy/enhancer-of-split related with YRPW motif

miRNAs

MicroRNAs

3′UTR

3′-untranslated region

CALCR

calcitonin receptor

MMP9

matrix metallopeptidase 9

c-Fos

FBJ osteosarcoma oncogene

TRAP

tartrate-resistant acid phosphatase

CTSK

cathepsin K

Notes

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (NSFC81371989 and NSFC81270967), Guangdong Science and Technology Department Project (2015A030313776, 2016A050503008), Shenzhen Municipal Science and Technology Innovation Committee Project (CXZZ20151015151249563, CXZZ20150401152251209, JCYJ20140416122812013 and JCYJ20150403101146318), General Research Fund of Research Grant Council of Hong Kong (RGC 715213 and RGC 17205714), Strategic Research Theme of Biomedical Engineering and Nanotechnology, Shenzhen Science and Technology Funding (JCYJ20160429185449249), Guangdong Scientific Plan (2014A030313743), and HK RGC (Ref No. T13-402/17-N).

Author contributions

(i) Design: T. Sun, S. Peng, and Z. Li; (ii) Acquisition of the data: T. Sun, Z. Li and Y. Feng; (iii) Analysis and interpretation of the data: T. Sun, Z. Li, S. Peng and Y. Feng; (iv) Figures: T. Sun; (v) Writing - original draft: T. Sun; (vi) Writing - review & editing: T. Sun and Z. Cai; (vii) Funding, resources and supervision: WW. Lu, S. Peng, Y. Feng and F. Leung; (viii) Experimental supports: X. Zhong, Z. Ning, T. Hou and L. Xiong.

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.

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Copyright information

© The International CCN Society 2018

Authors and Affiliations

  1. 1.Department of Spine Surgery, Shenzhen People’s HospitalJinan University Second College of MedicineShenzhenChina
  2. 2.Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of MedicineThe University of Hong KongHong KongChina
  3. 3.School of Materials Science and EngineeringTianjin UniversityTianjinChina
  4. 4.Department of TraumatologyGeneral Hospital of Ningxia Medical UniversityYinchuanChina

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