LncRNA-COX2 inhibits Fibroblast Activation and Epidural Fibrosis by Targeting EGR1

Abstract

Rationale: Epidural fibrosis is one of the contributors to failed back surgery syndrome (FBSS) with a high incidence of about 80,000 cases per year. The fibrosis spreads from the operative region to the dura mater or the nerve root and results in functional incapacity and pain after laminectomy. Our previous study showed that down-regulation of lncRNA-COX2 is involved in the epidural scar formation. However, it remains unknown whether lncRNA-COX2 participate in the fibroblast activation and epidural fibrogenesis. Methods: LncRNA-COX2 and EGR1 expression were assessed by qRT-PCR and western blotting. Fibroblasts differentiation, proliferation and migration was determined by Collagen I/ɑ-SMA, 5-ethynyl-2'-deoxyuridine (EdU) and Transwell Assay respectively. Luciferase reporter assay was performed for the verification of target of LncRNA-COX2. Laminectomy was performed to establish the model of epidural fibrosis in mice. Epidural scar was evaluated by hematoxylin and eosin (HE) staining and Masson Trichrome staining. Results: Based on the result of transcriptome profiling, we found LncRNA-COX2 was significantly decreased in epidural tissues after laminectomy and in activated fibrotic fibroblasts. In vitro, overexpression of LncRNA-COX2 suppressed epidural fibrogenesis by inhibiting fibroblasts differentiation, proliferation and migration. Mechanistically, LncRNA-COX2 functioned as competing endogenous RNA (ceRNA) of EGR1. Gain of LncRNA-COX2 significantly decreased the expression of EGR1 and showed anti-fibrotic effect while EGR1 was markedly increased after loss of LncRNA-COX2. In vivo, LncRNA-COX2 attenuated laminectomy-induced epidural fibrosis in mice. Conclusion:In summary, the results demonstrated that LncRNA-COX2 showed anti-fibrotic effect by targeting EGR1 and identified LncRNA-COX2 as therapeutic molecule for preventing aberrant epidural fibrosis.

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“…Wu et al indicated that Egr1 is essential for myofibroblast transdifferentiation and the wound healing process [ 72 ]. An in vitro study demonstrated that the lncRNA COX prevents aberrant epidural fibrosis by targeting Egr1 [ 73 ]. TGF-β is a major factor driving fibrosis progression.…”

LncRNA-mediated ceRNA network reveals the mechanism of action of Saorilao-4 decoction against pulmonary fibrosis

“…In a recent study, lncRNA-COX2 was shown to act as a ceRNA in EGR1. An increase in LncRNA-COX2 significantly reduces the expression of EGR1, displays anti-fibrotic effects, and has been identified as a therapeutic molecule for preventing abnormal epidural fibrosis ( Yang et al, 2022 ). Importantly, overexpression of PFAL inhibited the expression of miR-18a, whereas silencing of PFAL had the opposite effect.…”

Chronic pain after spine surgery: Insights into pathogenesis, new treatment, and preventive therapy

“…Excessive scar tissue may invade the spinal canal causing mechanical compression of nerve roots after laminectomy and spinal surgery, and it may also cause post-laminectomy epidural adhesion to the dura mater. These changes may lead to chronic back pain and functional incapacity and increase the risks of complications during revision surgery [ 24 ].…”

“…In some chronic pain patients, opioids are often the only analgesic that can help to relieve pain. However, the aforementioned systematic review reported that approximately 80% of patients experienced at least one major side effect, with constipation (41%), nausea (32%), and somnolence (29%) being the most common ones [ 24 ]. In addition, opioids are highly addictive and susceptible to abuse, and more than half of regular opioid users still suffer significant low back pain and radicular pain [ 85 ].…”

“…Most recently, long non-coding RNAs (LncRNAs) that inhibit COX2 expression (LncRNA-COX2) were shown to be decreased in epidural tissues after laminectomy and in activated fibrotic fibroblasts. Importantly, overexpression of LncRNA-COX2 attenuated laminectomy-induced epidural fibrosis in mice, by decreasing the expression of EGR1 and inhibiting fibroblasts differentiation, proliferation, and migration [ 24 ]. Thus, postoperative treatment with LncRNA-COX2 may prevent aberrant epidural fibrosis.…”