Botulinum toxin type A suppresses pro-fibrotic effects via the JNK signaling pathway in hypertrophic scar fibroblasts

Abstract

Hypertrophic scar is a dermal fibroproliferative disease characterized by the overproduction and deposition of extracellular matrix, and the hyperproliferation and enhanced angiogenesis of fibroblasts, along with their enhanced differentiation to myofibroblasts. Botulinum toxin type A shows potential for prevention of hypertrophic scar formation; however, its effectiveness in attenuating skin fibrosis and the related mechanism are unclear. In this study, human scar fibroblasts were cultured and stimulated with botulinum toxin type A, and the changes in fibroblast proliferation, migration, and protein expression of pro-fibrotic factors were evaluated with colorimetric, scratch, and enzyme-linked immunosorbent assays and western blotting, respectively. Botulinum toxin type A treatment decreased the proliferation and migration of human scar fibroblasts compared with those of untreated controls. Protein expression levels of pro-fibrotic factors (transforming growth factor β1, interleukin-6, and connective tissue growth factor) were also inhibited by botulinum toxin type A, whereas the JNK phosphorylation level was increased. Activation of the JNK pathway demonstrated the inhibitory effects of the toxin on human scar fibroblast proliferation and production of pro-fibrotic factors, suggesting that the suppressive effects of botulinum toxin type A are closely associated with JNK phosphorylation. Overall, this study showed that botulinum toxin type A has a suppressive effect on extracellular matrix production and scar-related factors in human scar fibroblasts in vitro, and that regulation of JNK signaling plays an important role in this process. Our results provide a theoretical basis, at the cellular level, for the therapeutic use of botulinum toxin type A.

Evidence‐based therapy in hypertrophic scars: An update of a systematic review

“…Another possible target substance, which has shown similar regulating mechanisms, is botulinum toxin type A 51 . Its theoretical mechanism of action has been shown to be in an inhibition of TGF‐b1 as well as in an increase of the JNK phosphorylation leading to reduced fibroblast proliferation and production of profibrotic factors, among others 52 . No level of evidence I studies have investigated this substance to date.…”

Botulinum toxin type A attenuates hypertrophic scar formation via the inhibition of TGF‐β1/Smad and ERK pathways

“…9 BTA has also been reported to suppress pro-fibrotic effects via the c-Jun N-terminal kinases (JNK) signaling pathway in hypertrophic scar fibroblasts in vitro. 10 However, the role of BTA on inhibiting HS formation through TGF-β1/Smad and MAPK pathways has not been determined. Therefore, the present study aimed to explore the potential mechanisms of BTA on the inhibition of HS formation.…”

“…It is reported that BTA can inhibit capsule formation through the TGF‐β1/Smad signaling pathway 9 . BTA has also been reported to suppress pro‐fibrotic effects via the c‐Jun N‐terminal kinases (JNK) signaling pathway in hypertrophic scar fibroblasts in vitro 10 . However, the role of BTA on inhibiting HS formation through TGF‐β1/Smad and MAPK pathways has not been determined.…”

lncRNA PAPPA-AS1 Induces the Development of Hypertrophic Scar by Upregulating TLR4 through Interacting with TAF15

“…lncRNA PAPPA-AS1 was picked out due to its high expression level in the HTsFb cells compared to NsFb. Fibroblasts are reported to be the main participants in the process and development of HTS by secreting collagens; the excessive proliferation of which is regarded as the main inducer for the formation of HTS [ 38 , 39 ]. Therefore, in the present study, HTsFb cells were taken as the study objects.…”