Effects of miR-335-5p in modulating osteogenic differentiation by specifically downregulating Wnt antagonist DKK1

Jin Zhang, Qisheng Tu, Lynda F. Bonewald, Xi He, Gary Stein, Jane Lian, Jake Chen

Research output: Contribution to journalArticlepeer-review

185 Scopus citations

Abstract

Dickkopf-related protein 1 (DKK1) is essential to maintain skeletal homeostasis as an inhibitor of Wnt signaling and osteogenic differentiation. The purpose of this study was to investigate the molecular mechanisms underlying the developmental stage-specific regulation of the DKK1 protein level. We performed a series of studies including luciferase reporter assays, micro-RNA microarray, site-specific mutations, and gain- and loss-of-function analyses. We found that the DKK1 protein level was regulated via DKK1 3' UTR by miRNA control, which was restricted to osteoblast-lineage cells. As a result of decreased DKK1 protein level by miR-335-5p, Wnt signaling was enhanced, as indicated by elevated GSK-3β phosphorylation and increased β-catenin transcriptional activity. The effects of miR-335-5p were reversed by anti-miR-335-5p treatment, which downregulated endogenous miR-335-5p. In vivo studies showed high expression levels of miR-335-5p in osteoblasts and hypertrophic chondrocytes of mouse embryos, indicating a pivotal role of miR-335-5p in regulating bone development. In conclusion, miR-335-5p activates Wnt signaling and promotes osteogenic differentiation by downregulating DKK1. This cell- and development-specific regulation is essential and mandatory for the initiation and progression of osteogenic differentiation. miR-335-5p proves to be a potential and useful targeting molecule for promoting bone formation and regeneration.

Original languageEnglish (US)
Pages (from-to)1953-1963
Number of pages11
JournalJournal of Bone and Mineral Research
Volume26
Issue number8
DOIs
StatePublished - Aug 2011

Keywords

  • DKK1
  • MIR-335-5P
  • Wnt
  • bone formation
  • osteogenic differentiation

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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