Expansion of Bone Precursors through Jun as a Novel Treatment for Osteoporosis-Associated Fractures

Stem Cell Reports. 2020 Apr 14;14(4):603-613. doi: 10.1016/j.stemcr.2020.02.009. Epub 2020 Mar 19.

Abstract

Osteoporosis and osteoporotic fractures lead to decreased life quality and high healthcare costs. Current treatments prevent losses in bone mass and fractures to some extent but have side effects. Therefore, better therapies are needed. This study investigated whether the transcription factor Jun has a specific pro-osteogenic potency and whether modulating Jun could serve as a novel treatment for osteoporosis-associated fractures. We demonstrate that ectopically transplanted whole bones and distinct osteoprogenitors increase bone formation. Perinatal Jun induction disturbs growth plate architecture, causing a striking phenotype with shortened and thickened bones. Molecularly, Jun induces hedgehog signaling in skeletal stem cells. Therapeutically, Jun accelerates bone growth and healing in a drilling-defect model. Altogether, these results demonstrate that Jun drives bone formation by expanding osteoprogenitor populations and forcing them into the bone fate, providing a rationale for future clinical applications.

Keywords: JUN; bone precursor expansion; bone precursors; fractures; osteoporosis; osteoprogenitors; skeletal stem cells; stem cell therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Development
  • Bone Transplantation
  • Bone and Bones / pathology*
  • Cell Differentiation
  • Cell Proliferation
  • Fracture Healing
  • Growth Plate / metabolism
  • Hedgehog Proteins / metabolism
  • Mice
  • Osteoporotic Fractures / metabolism*
  • Osteoporotic Fractures / pathology*
  • Phenotype
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Signal Transduction
  • Stem Cells / metabolism*

Substances

  • Hedgehog Proteins
  • Proto-Oncogene Proteins c-jun