Anti‑apoptotic effects of glycosaminoglycans via inhibition of ERK/AP‑1 signaling in TNF‑α‑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‑α (TNF‑α)‑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‑α‑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‑α‑stimulated HDFs. In addition, GAGs attenuated the apoptosis of HDFs induced by TNF‑α. The current study revealed a novel mechanism: GAGs serve a crucial role in ameliorating TNF‑α‑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.

The effect of aging in primary human dermal fibroblasts

“…Both the dermis and epidermis are affected by sunlight and UV radiation exposure [10; 11]. Skin cells exhibit complex alterations during aging and are frequently accompanied or caused by changes in gene expression and the susceptibility of cell transformation [12; 13], related to extracellular matrix proteins [14; 15; 16]. The areas exposed to the sunlight display, in general, deep and fine lines, wrinkles, rough and dry skin, alterations in skin pigmentation as dark spots, sagging, and tensile strength loss [17; 18].…”

Crude protein from spirulina increases the viability of CCD‑986sk cells via the EGFR/MAPK signaling pathway

“…Furthermore, three-dimensional alteration of elastic fibers indicates the marked and continuous upregulation of an elastin-degrading enzyme in the aging skin. The ECM of the dermis consists of collagen and is produced by fibroblasts (15). In particular, type I collagen is the most prevalent of the fibril-forming collagens (16,17).…”

Effects of the collagen–glycosaminoglycan mesh on gene expression as determined by using principal component analysis-based unsupervised feature extraction

“…The top ranked term in GO biological process (BP) (Table 2) is “regulation of apoptotic process”. Na et al reported [9] that collagen–glycosaminoglycan has an anti-apoptosis effect. Thus, the fact that this term is ranked first is reasonable.…”