Fifty-kDa Hyaluronic Acid Upregulates Some Epidermal Genes without Changing TNF-α Expression in Reconstituted Epidermis

Abstract

Background: Due to its strong water binding potential, hyaluronic acid (HA) is a well-known active ingredient for cosmetic applications. However, based on its varying molecular size, skin penetration of HA may be limited. Recent studies have demonstrated that low-molecular-weight HA (LMW HA) may show a certain proinflammatory activity. We thus aimed to characterize an LMW-sized HA molecule that combines strong anti-aging abilities with efficient skin penetration but lacks potential proinflammatory effects. Methods: Total RNA and total protein were isolated from reconstituted human epidermis following incubation with HAs of various molecular weights (20, 50, 130, 300, 800 and 1,500 kDa). Tumor necrosis factor-α expression was determined using quantitative PCR. Genomic and proteomic expression of various junctional proteins was determined using Affymetrix and common Western blotting techniques. Results: LMWHA of approximately 50 kDa did not significantly alter tumor necrosis factor-α expression compared to 20-kDa HA, but revealed significantly higher skin penetration rates than larger sized HA associated with increased expression of genes and proteins known to be involved in tight junction formation and keratinocyte cohesion. Conclusion: LMW HA of approximately 50 kDa shows better penetration abilities than larger-sized HA. In addition, LMW HA influences the expression of various genes including those contributing to keratinocyte differentiation and formation of intercellular tight junction complexes without showing proinflammatory activity. These observations contribute to current knowledge on the effects of LMW HA on keratinocyte biology and cutaneous physiology.

Hyaluronan Metabolism in Human Keratinocytes and Atopic Dermatitis Skin Is Driven by a Balance of Hyaluronan Synthases 1 and 3

“…Our results thus clarify the discrepancy in the literature about the link between HA and keratinocyte differentiation. Some publications report that HA induces differentiation (Bourguignon et al, 2006;Farwick et al, 2011), whereas others demonstrate that HA inhibits differentiation (Maytin et al, 2004;Passi et al, 2004). Our study suggests HA is not involved in the process of spontaneous epidermal differentiation.…”

“…In the latter, HA is mainly localized around the cells of basal and spinous layers (Tuhkanen et al, 1998). Involvement of HA and HASs in proliferation, differentiation, and migration of keratinocytes, as well as in the establishment of the epidermal barrier, has been reported (Maytin et al, 2004;Passi et al, 2004;Rilla et al, 2004;Bourguignon et al, 2006;Farwick et al, 2011). Yet, the mechanisms of HA involvement in normal epidermis are not well identified or understood.…”

Hyaluronan metabolism enhanced during epidermal differentiation is suppressed by vitamin C

“…How abundant these fragments are in vivo , and whether they are produced for a specific biological purpose, is unknown. Interestingly, ~50‐kDa hyaluronan fragments appear to promote the expression of genes related to epidermal differentiation and tight junction complexes . The small fragments may also have signalling functions for dermal cells, or they could accumulate in the stratum corneum, affecting barrier characteristics, and enhance bacterial defence mechanisms in skin by inducing the secretion of β‐defensins via activation of Toll‐like receptors (TLRs) .…”

A Placebo-Controlled Study Demonstrates the Long-Lasting Anti-Aging Benefits of a Cream Containing Retinol, DihydroxyMethylChromone (DMC) and Hyaluronic Acid

“…Several publications demonstrate that fragments of HA could also play a role in the epidermal physiology, by binding to specific receptors such as CD44, expressed on keratinocyte, and that topical use of HA fragments of around 50 -400 kd could reverse epidermal atrophy in mice [35]. Also, it has been demonstrated recently that low molecular weight HA fragments of 50 kd could be delivered in reconstructed epidermis, and induced expression of different genes implicated in the terminal differentiation of keratinocytes, such as claudin and occludin genes [36]. Thus, low molecular weight fragments of HA, contained in our product, could also complement the effect of retinol on the keratinocytes, and complement its action to deliver improvement of skin aging signs, such as fine lines and radiance.…”