miR‑519d‑3p promotes TGFβ/Smad mediated postoperative epidural scar formation via suppression of BAMBI

Abstract

To investigate the role of microrna (mir)-519d-3p in postoperative epidural scar formation and its regulation of the bone morphogenetic protein and activin membrane-bound inhibitor (BaMBi), mir-519d-3p and BaMBi expression levels in the lumbar disc of patients who had undergone laminectomy were detected with reverse transcription-quantitative polymerase chain reaction and western blotting. The results demonstrated that miR-519d-3p expression was significantly increased, whereas BaMBi expression was sharply reduced in the lumbar discs of patients suffering from epidural scars. Subsequently, the mir-519d-3p mimic was transfected into primary fibroblasts isolated from epidural scar tissues. Flow cytometric and cell countin Kit-8 analyses indicated that overexpression of mir-519d-3p promoted the proliferation of fibroblasts, the production of tumor necrosis factor-α and interleukin (il)-1α, and the expression of type i collagen (col i), α-smooth muscle actin (α-SMA) and fibronectin (FN). downregulation of mir-519d-3p by the mir-519d-3p antagomir transfection had the opposite effect. Bioinformatics and luciferase reporter gene analyses demonstrated that BaMBi is a target gene of mir-519d-3p: mir-519d-3p directly binds to the 3'-untranslated region of BaMBi mrna and suppressed BAMBI protein expression. Finally, the pcDNA-BAMBI vector and BaMBi small interfering rna were respectively transfected into primary fibroblasts to overexpress and knockdown the BaMBi gene. it was demonstrated that BaMBi overexpression suppressed fibroblast proliferation, TNF-α and il-1α production, and the expression of col i, α-SMa and FN proteins, whereas, BAMBI knockdown had the opposite effect. in conclusion, it was noted that BaMBi is a target of mir-519d-3p and mir-519d-3p promotes transforming growth factor β/mothers against decapentaplegic homolog 9-mediated postoperative epidural scar formation via suppression of BaMBi.

Increased Levels of BAMBI Inhibit Canonical TGF-β Signaling in Chronic Wound Tissues

“…For example, BAMBI has been shown to inhibit skin fibrosis in keloids by suppressing TGF-β1-induced hyper normal fibroblast proliferation and excessive type I collagen accumulation [ 39 ]. Consistent with this finding, suppression of BAMBI by miR-519d-3p promoted TGFβ/Smad-mediated postoperative epidural scar formation [ 40 ]. Modulation of BAMBI, however, not only affected ECM formation.…”

MicroRNA-29a Mitigates Laminectomy-Induced Spinal Epidural Fibrosis and Gait Dysregulation by Repressing TGF-β1 and IL-6

“…A growing body of evidence suggests that microRNA signaling plays a vital role in fibroblast cellular behavior and the development of fibrotic activity originating from surgical scar tissue [37]. In addition, miR-519d-3p [38] and miR-146 [39] may serve as diagnostic biomarkers for the early detection of epidural fibrosis and further upregulation of enhanced fibroblast proliferation and inflammatory response in epidural fibrosis.…”

The clinical significance and function of miR-146 in the promotion of epidural fibrosis

“…In previous mechanism studies it was reported that transforming growth factor (TGF)β signaling is a key factor in the regulation of fibrosis (Meng et al, 2016). miR-27 and miR-519d were confirmed to mediate fibroblast activation and epidural fibrosis by targeting the TGFβ signaling pathway (Zeng et al, 2017;Yang L et al, 2019). Besides, the accumulation of collagen was also a principal cause of epidural fibrosis.…”

“…However, miRNAs could negatively regulate the expression of target genes by binding to the 3'UTR of target mRNA molecules, thus miRNAs have been reported to be involved in various biological processes, such as carcinogenesis (Chen et al, 2019;Nariman-Saleh-Fam et al, 2019), anticancer effect (Tao et al, 2018;Yang J et al, 2020), neuro-protection (Song et al, 2019;Xiao et al 2019), as well as epidural fibrosis (Lin et al, 2018). For example, an investigation on the role of miR-519d-3p in postoperative epidural scar formation and found that the overexpression of miR-519d-3p promoted the proliferation of fibroblasts and the expression of type I collagen, which are important factors in epidural fibrosis (Yang L et al, 2019). Previously, it has been demonstrated that the prolapse of the intervertebral nucleus pulposus would lead to an epidural inflammation (McCarron et al, 1987).…”