Suberoylanilide hydroxamic acid attenuates epidural fibrosis via inhibiting myofibroblast differentiation and increasing fibroblast apoptosis

J.-S. Yang, P. Liu, J.-J. Liu, L. Chu, J. Li, C. Chen, L. Yan, T.-J. Liu, H. Chen, D.-J. Hao

Department of Spine Surgery, Honghui Hospital, Xi’an Jiaotong University, Xi’an, China. dingjun.hao@qq.com

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• Pharmacology

OBJECTIVE: Epidural fibrosis represents a fatal stage of failed back surgery syndrome (FBSS) of known and idiopathic etiology, but no valid therapy is presently available. Previous evidence demonstrated that suberoylanilide hydroxamic acid (SAHA), a histone deacetylases inhibitor, has antifibrotic and anti-inflammatory potential. Current studies have proved that SAHA inhibits myofibroblast differentiation and increases fibroblast apoptosis to attenuate epidural fibrosis. The purpose of this study was to investigate the effect and mechanism of SAHA on repressing epidural fibrosis.
PATIENTS AND METHODS: First, the levels of acetylation of histone and α-tubulin in adult human fibroblasts (AHF) and human epidural fibroblasts (HEF) were analyzed following SAHA and transforming growth factor-β(TGF-β) treatment. Then, mRNA and protein obtained from human fibroblasts following TGF-β activation and SAHA treatment in vitro culture were used to test the influence of SAHA on the activation and apoptosis of fibroblasts, so as to further explore the related mechanism of SAHA. Then, a laminectomy model was established in rats to observe the therapeutic effect of SAHA on epidural scar tissue.
RESULTS: The present research proved that the increases of HDAC 3 and α-tubulin were observed in AHF and HEF after TGF-β administration, but SAHA decreased HDAC 3 and α-tubulin expressions. In addition, cell study demonstrated that SAHA inhibited fibroblast activation via decreasing TGF-β function and accelerated apoptosis by promoting cleaved-caspase-3. In the epidural fibrosis model, it was found that SAHA weakened scar hyperplasia and collagen deposition, and effectively inhibited the process of epidural fibrosis.
CONCLUSIONS: These results indicated that SAHA inhibited HDAC 3 expression, decreased TGF-β effect, and enhanced caspase-3 in fibroblasts, leading reduction of myofibroblast activation and apoptosis elevation. Hence, SAHA ameliorated epidural fibrosis development.

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