IL-1β inhibits osteogenesis of human bone marrow-derived mesenchymal stem cells by activating FoxD3/microRNA-496 to repress wnt signaling

Genesis. 2017 Jul;55(7). doi: 10.1002/dvg.23040. Epub 2017 Jun 5.

Abstract

IL-1β, a major cytokine of proinflammatory response, has been implicated in bone loss. However, its effects on mesenchymal progenitor cells-associated bone regeneration remain elusive. Here, we investigated the role of microRNA for the regulation of osteogenesis by IL-1β in human bone marrow-derived mesenchymal stem cells (hBMMSC). Our data suggested Homo sapiens (hsa)-miR-496 is induced by IL-1β in hBMMSC and mediates the decreased β-catenin expression. Reporter assays using the 3'-UTR of β-catenin demonstrated sequence-dependent gene suppression with hsa-miR-496. IL-1β activated hsa-miR-496 expression through a transcription factor, Foxhead box D3 protein (FoxD3). The activation of hsa-miR-496 promoter in hBMMSC depended on a consensus FoxD3 binding motif. Under osteogenic differentiation, IL-1β treatment or overexpressing hsa-miR-496 attenuated bone mineralization and bone marker gene expressions in hBMMSC. Further, anti-miR-496 rescued the inhibitory effects of IL-1β. Our findings suggest a pivotal role of hsa-miR-496 in linking inflammation to impaired bone regeneration, and provide a rationale for using appropriate hsa-miR-496 inhibitors in the treatment of inflammation-associated bone loss.

Keywords: inflammation; mesenchymal stem cell; microRNA; osteogenesis; β-catenin.

MeSH terms

  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Humans
  • Interleukin-1beta / pharmacology*
  • Mesenchymal Stem Cells / cytology*
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / metabolism
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Osteogenesis / drug effects*
  • Wnt Signaling Pathway*
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • FOXD3 protein, human
  • Forkhead Transcription Factors
  • Interleukin-1beta
  • MIRN496 microRNA, human
  • MicroRNAs
  • beta Catenin