Pleiotropic FTY720 Is a Specific and Potent Therapy for Hypertrophic Scars

Abstract

Hypertrophic scarring (HS) is a fibrotic skin condition characterized by aberrant fibroblast phenotypes and excessive deposition of extracellular matrix components. 2-Amino-2-[2-(4-octylphenyl)]-1, 3-propanediol hydrochloride (FTY720), an immunomodulator approved for treating multiple sclerosis, is reported to attenuate fibrosis in multiple disease models. Here we found that FTY720 could significantly attenuate the proliferation and fibrosis in HS fibroblasts (HSFs) and in an animal HS model. Upon treating HSFs or normal dermal fibroblasts with FTY720 at different concentrations for different time periods, we found that FTY720 presented a pleiotropic effect specifically on HSFs but not NFs, including reducing cell viability, arresting cell cycle progression at the G0/G1 phase, promoting apoptosis, inhibiting migration and contraction, and suppressing the expressions of α-smooth muscle actin, collagen I, and collagen III. Mechanistic studies showed that the antifibrotic activities of FTY720 were potentially mediated through sphingosine 1-phosphate receptor 5 to inhibit the protein kinase B/mTOR/p70S6K, but not the Smad, signaling pathway. The in vitro actions of FTY720 also translated into a rabbit ear HS model, stimulating the healing of HS. These findings collectively suggest that FTY720 targets multiple phenotypes of HSFs and is a promising therapeutic agent for HS.