Abstract
BackgroundThe prevention of surgery-induced intraarticular fibrosis remains a challenge following orthopedic surgery. Homoharringtonine (HHT) has been reported to have positive effects in preventing various kinds of fibrosis. However, little is known regarding its effect as well as the potential mechanism of HHT in preventing surgery-induced intraarticular fibrosis.MethodsVarious concentrations of HHTs were locally applied in vivo to reduce knee intraarticular fibrosis in rabbits. Histological macroscopic assessments such as hematoxylin and eosin (HE) staining, Masson’s trichrome staining, and Picric-sirius red polarized light were used to evaluate the effect of HHT in reducing intraarticular fibrosis. CCK-8, cell cycle assay, and EdU incorporation assay were used in vitro to detect HHT’s effect on inhibiting fibroblast viability and proliferation. The effect of HHT on fibroblast differentiation, extracellular matrix production, and apoptosis were evaluated by western blot, flow cytometry, immunofluorescent staining, and TUNEL analysis. Moreover, the expressions of PI3K/AKT/mTOR signaling pathway were detected.ResultsThe results demonstrated that HHT could reduce the formation of intraarticular fibrosis. HHT was also found to induce fibroblast apoptotic cell death in a dose- and time-dependent manner in vitro. Moreover, HHT could effectively inhibit the production of the extracellular matrix secreted by fibroblasts and inhibited the expression of p-PI3K, p-AKT, and p-mTOR in a dose-dependent manner. After treating with insulin-like growth factor-1 (IGF-1), an activator of the PI3K/AKT axis, the expressions of pro-apoptosis-related proteins were decreased, and the fibroblast apoptosis rate was also inhibited.ConclusionsIn conclusion, this study demonstrated that HHT could reduce the formation of intraarticular fibrosis through the inhibition of fibroblast proliferation, extracellular matrix production, and the induction of fibroblast apoptotic cell death. Furthermore, its potential mechanism may be through the suppression of the PI3K/AKT/mTOR signaling pathway.
Highlights
The prevention of surgery-induced intraarticular fibrosis remains a challenge following orthopedic surgery
In conclusion, this study demonstrated that HHT could reduce the formation of intraarticular fibrosis through the inhibition of fibroblast proliferation, extracellular matrix production, and the induction of fibroblast apoptotic cell death
Its potential mechanism may be through the suppression of the PI3K/AKT/mTOR signaling pathway
Summary
The prevention of surgery-induced intraarticular fibrosis remains a challenge following orthopedic surgery. Many strategies, including arthroscopically assisted knee arthrolysis, injection of drugs into the knee joint, and functional exercise of the knee joint were used for this regard [5, 6]. Such methods have limitations and side effects; a reasonable, effective, and simple method conferring little side effects to prevent intraarticular fibrosis scar adhesion is urgently needed. Numerous studies have shown that various anti-proliferative drugs, such as hydroxycamptothecin and mitomycin C, are satisfactory in reducing fibrosis scar adhesion through the inhibition of fibroblast proliferation [8]. Certain studies have illustrated that effective prevention of fibrosis scar adhesion could be achieved through the promotion of fibroblast apoptosis [9]
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