Anti-apoptotic effects of glycosaminoglycans via inhibition of ERK/AP-1 signaling in TNF-alpha-stimulated human dermal fibroblasts

Abstract

It has been established that glycosaminoglycans (GAGs) serve an important role in protecting the skin against the effects of aging. A previous clinical trial by our group identified that a cream containing GAGs reduced wrinkles and increased skin elasticity, dermal density and skin tightening. However, the exact molecular mechanism underlying the anti-aging effect of GAGs has not yet been fully elucidated. The present study assessed the influence of GAGs on cell viability, collagen synthesis and collagen synthesis-associated signaling pathways in tumor necrosis factor- (TNF-)-stimulated human dermal fibroblasts (HDFs); an in vitro model of aging. The results demonstrated that GAGs restored type I collagen synthesis and secretion by inhibiting extracellular signal-regulated kinase (ERK) signaling in TNF--stimulated HDFs. However, GAGs did not activate c-jun N-terminal kinase or p38. It was determined that GAGs suppressed the phosphorylation of downstream transcription factors of ERK activation, activator protein-1 (AP-1; c-fos and c-jun), leading to a decrease in matrix metalloproteinase-1 (MMP-1) levels and the upregulation of tissue inhibitor of metalloproteinase-1 in TNF--stimulated HDFs. In addition, GAGs attenuated the apoptosis of HDFs induced by TNF-. The current study revealed a novel mechanism: GAGs serve a crucial role in ameliorating TNF--induced MMP-1 expression, which causes type I collagen degeneration via the inactivation of ERK/AP-1 signaling in HDFs. The results of the present study indicate the potential application of GAGs as effective anti-aging agents that induce wrinkle reduction.