Mocetinostat suppresses epidural fibrosis following laminectomy by inhibiting myofibroblast activation and increasing apoptosis

W.-J. Wu, J. Wang, J. Liang, Q. Zhou, Y. Liang

Department of Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. Ly10334@rjh.com.cn

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• Pharmacology

OBJECTIVE: To investigate the effect and mechanism of mocetinostat on diminishing epidural fibrosis. Dysregulated wound repair usually occurs after injury or surgery and is featured by excessive scar tissue contributed by fibrosis. Increasing researches demonstrated that histone acetylation, an epigenetic alteration, plays a crucial role in fibrosis. However, the mechanism of the complicated process remains unclear. In the current study, the effect of histone deacetylase (HDAC) inhibitor mocetinostat in a rat model of epidural fibrosis was detected, and it was discovered that mocetinostat suppressed myofibroblast activation and increased apoptosis by reducing Akt/GSK3b signaling.
PATIENTS AND METHODS: First, the levels of histone acetylation in the patients’ epidural fibroblasts were analyzed. Then, mRNAs and proteins obtained from human fibroblasts following TGF-β activation and mocetinostat treatment in vitro were used to examine the influence of mocetinostat on the activation and survival of fibroblasts, so as to explore the related mechanism of mocetinostat. The laminectomy model was established in rats to observe the therapeutic effect of mocetinostat on epidural scar tissues.
RESULTS: In this research, it was found that the increase of HDAC1 in human dura scar was accompanied by the aggravation of fibrosis. In addition, cell assay demonstrated that mocetinostat inhibited fibroblast activation and accelerated apoptosis by inhibiting Akt/GSK3b pathway. In the rat model, mocetinostat weakened scar hyperplasia and collagen deposition and effectively inhibited the process of epidural fibrosis.
CONCLUSIONS: The above results indicate that mocetinostat inhibits HDAC1 expression and decreases the conduction of the AKT/GSK3b pathway in fibroblasts, leading to myofibroblast activation and apoptosis elevation. Hence, mocetinostat ameliorates epidural fibrosis.

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