Metformin attenuates post-epidural fibrosis by inhibiting the TGF-β1/Smad3 and HMGB1/TLR4 signaling pathways

J Cell Mol Med. 2021 Apr;25(7):3272-3283. doi: 10.1111/jcmm.16398. Epub 2021 Feb 21.


Excessive post-epidural fibrosis is a common cause of recurrent back pain after spinal surgery. Though various treatment methods have been conducted, the safe and effective drug for alleviating post-epidural fibrosis remains largely unknown. Metformin, a medicine used in the treatment of type 2 diabetes, has been noted to relieve fibrosis in various organs. In the present study, we aimed to explore the roles and mechanisms of metformin in scar formation in a mouse model of laminectomy. Post-epidural fibrosis developed in a mouse model of laminectomy by spinous process and the T12-L2 vertebral plate with a rongeur. With the administration of metformin, post-epidural fibrosis was reduced, accompanied with decreased collagen and fibronectin in the scar tissues. Mechanistically, metformin decreased fibronectin and collagen deposition in fibroblast cells, and this effect was dependent on the HMGB1/TLR4 and TGF-β1/Smad3 signalling pathways. In addition, metformin influenced the metabolomics of the fibroblast cells. Taken together, our study suggests that metformin may be a potential option to mitigate epidural fibrosis after laminectomy.

Keywords: HMGB1; TGF-β1; epidural fibrosis; metabolomics; metformin; spine operation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Failed Back Surgery Syndrome / drug therapy*
  • Failed Back Surgery Syndrome / metabolism
  • Failed Back Surgery Syndrome / pathology
  • Fibrosis
  • HMGB1 Protein / metabolism*
  • Humans
  • Male
  • Metformin / pharmacology
  • Metformin / therapeutic use*
  • Mice
  • Mice, Inbred C57BL
  • NIH 3T3 Cells
  • Signal Transduction / drug effects
  • Smad3 Protein / metabolism*
  • Toll-Like Receptor 4 / metabolism*
  • Transforming Growth Factor beta / metabolism*


  • HMGB1 Protein
  • Smad3 Protein
  • Toll-Like Receptor 4
  • Transforming Growth Factor beta
  • Metformin