MiR-497∼195 Cluster Regulates Angiogenesis During Coupling With Osteogenesis by Maintaining Endothelial Notch and HIF-1α Activity

Nat Commun. 2017 Jul 7;8:16003. doi: 10.1038/ncomms16003.

Abstract

A specific bone vessel subtype, strongly positive for CD31 and endomucin (CD31hiEmcnhi), is identified as coupling angiogenesis and osteogenesis. The abundance of type CD31hiEmcnhi vessels decrease during ageing. Here we show that expression of the miR-497∼195 cluster is high in CD31hiEmcnhi endothelium but gradually decreases during ageing. Mice with depletion of miR-497∼195 in endothelial cells show fewer CD31hiEmcnhi vessels and lower bone mass. Conversely, transgenic overexpression of miR-497∼195 in murine endothelium alleviates age-related reduction of type CD31hiEmcnhi vessels and bone loss. miR-497∼195 cluster maintains the endothelial Notch activity and HIF-1α stability via targeting F-box and WD-40 domain protein (Fbxw7) and Prolyl 4-hydroxylase possessing a transmembrane domain (P4HTM) respectively. Notably, endothelialium-specific activation of miR-195 by intravenous injection of aptamer-agomiR-195 stimulates CD31hiEmcnhi vessel and bone formation in aged mice. Together, our study indicates that miR-497∼195 regulates angiogenesis coupled with osteogenesis and may represent a potential therapeutic target for age-related osteoporosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antagomirs / genetics
  • Antagomirs / metabolism
  • Aptamers, Nucleotide / genetics
  • Aptamers, Nucleotide / metabolism
  • Bone Density
  • Bone and Bones / blood supply
  • Bone and Bones / metabolism
  • Bone and Bones / pathology
  • F-Box-WD Repeat-Containing Protein 7 / genetics
  • F-Box-WD Repeat-Containing Protein 7 / metabolism
  • Gene Expression Regulation, Developmental
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Mice
  • Mice, Knockout
  • MicroRNAs / agonists
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Molecular Targeted Therapy
  • Neovascularization, Physiologic / genetics
  • Osteogenesis / genetics
  • Osteoporosis / genetics
  • Osteoporosis / metabolism
  • Osteoporosis / pathology
  • Osteoporosis / therapy*
  • Platelet Endothelial Cell Adhesion Molecule-1 / agonists
  • Platelet Endothelial Cell Adhesion Molecule-1 / genetics*
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Prolyl Hydroxylases / genetics
  • Prolyl Hydroxylases / metabolism
  • Receptor, Notch1 / genetics*
  • Receptor, Notch1 / metabolism
  • Sialoglycoproteins / agonists
  • Sialoglycoproteins / genetics*
  • Sialoglycoproteins / metabolism
  • Signal Transduction

Substances

  • Antagomirs
  • Aptamers, Nucleotide
  • Emcn protein, mouse
  • F-Box-WD Repeat-Containing Protein 7
  • Fbxw7 protein, mouse
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • MicroRNAs
  • Notch1 protein, mouse
  • Pecam1 protein, mouse
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Receptor, Notch1
  • Sialoglycoproteins
  • mirn497 microRNA, mouse
  • Prolyl Hydroxylases