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.

Recently, various immunosuppressant drugs have been shown to induce hair growth in normal hair as well as in alopecia areata and androgenic alopecia; however, the responsible mechanism has not yet been fully elucidated. In this study, we investigate the influence of mycophenolate (MPA), an immunosuppressant, on the proliferation of human dermal papilla cells (hDPCs) and on the growth of human hair follicles following catagen induction with interferon (IFN)-γ. IFN-γ was found to reduce β-catenin, an activator of hair follicle growth, and activate glycogen synthase kinase (GSK)-3β, and enhance expression of the Wnt inhibitor DKK-1 and catagen inducer transforming growth factor (TGF)-β2. IFN-γ inhibited expression of ALP and other dermal papillar cells (DPCs) markers such as Axin2, IGF-1, and FGF 7 and 10. MPA increased β-catenin in IFN-γ-treated hDPCs leading to its nuclear accumulation via inhibition of GSK3β and reduction of DKK-1. Furthermore, MPA significantly increased expression of ALP and other DPC marker genes but inhibited expression of TGF-β2. Therefore, we demonstrate for the first time that IFN-γ induces catagen-like changes in hDPCs and in hair follicles via inhibition of Wnt/β-catenin signaling, and that MPA stabilizes β-catenin by inhibiting GSK3β leading to increased β-catenin target gene and DP signature gene expression, which may, in part, counteract IFN-γ-induced catagen in hDPCs.