Abstract

TNC was elevated in the epidural scar tissues either in the patients after spine surgery or in a murine laminectomy model. • Ablation of TNC via knockout significantly reduced epidural scar formation pointing at an important role of TNC in fibrosis shown to be linked to elevated fibronectin expression. • Through its Epidermal Growth Factor Like (EGFL) domains, TNC downregulates caveolin-1 involving Toll‑like receptor 4 (TLR4). • By downregulating caveolin-1, TNC relieves suppression of transforming growth factor‑β receptor I (TβRI), resulting in a profibrotic fibroblast phenotype with upregulated fibronectin expression. Excessive deposition of extracellular matrix (ECM) following laminectomy contributes to epidural scar formation, which is associated with postoperative lumbodorsal pain. This study aimed to investigate the role and mechanisms of the ECM glycoprotein tenascin-C (TNC) in epidural scar formation using a murine laminectomy model. TNC was significantly increased in the epidural scarring tissues from the patients recovered after spine operation. As similar, the epidural scar was enriched with TNC in a mouse model of laminectomy. TNC promoted the activation of fibroblasts. In addition to the membrane receptor Toll-like receptor 4 (TLR4), TNC directly bind with Caveolin-1 via its EGFL domain. Mechanistically, TNC/Caveolin-1 suppressed transforming growth factor-β receptor I (TβRI) activity, thereby enhancing fibronectin synthesis in fibroblasts. In the mouse model of epidural fibrosis, TNC-knockout (TNC-KO) significantly reduced epidural scar formation accompanied by decreased collagen deposition and fibronectin (Fn) content within scar tissue. In conclusion, our findings highlight TNC as a critical mediator of epidural fibrosis, and anti-TNC therapeutics may represent a promising strategy to mitigate postoperative epidural scarring.