Hyaluronan in the Skin: Mechanisms of Age-Dependent and UVA-Provoked Down-Regulated Secretion of Hyaluronan by Human Dermal Fibroblasts and Prospective Agents to Ameliorate the Hyaluronan Deficiency in Chronologically Aged Skin and Photo-aged Skin | Book Publisher International

 Hyaluronan (HA) is an extracellular matrix glycosaminoglycan that is abundant in the dermis and is essential for the skin's physicochemical and mechanical qualities. The cellular mechanism(s) behind the age-related HA deficit in the dermis of old skin are unknown. We first investigated the effects of chronological ageing and UV A irradiation on the secretion of HA by human dermal fibroblasts (NHDFs), as well as the cellular and intracellular signalling mechanisms that control its synthesis and degradation by enzymes such as HA synthases (HAS), hyaluronidases (HYAL), and HYaluronan Binding protein Involved in HA Depolymerization (HYBID). These findings suggest that the age-related shortage of HA in the dermis is caused by a down-regulation in the ability of NHDFs to secrete HA, and that the decrease in secretion is mostly due to down-regulated expression of HASs, particularly HAS2. UVA radiation, on the other hand, was discovered to restrict the secretion of HA by NHDFs, as evidenced by the down- and up-regulation of HAS2 mRNA and protein levels, as well as the HA-degrading protein, HYBID, respectively. UVA exposure activates the p38/MSK1/CREB/c-Fos/AP-1 axis, the JNK/c-Jun axis, and the p38/ATF-2 axis, but down-regulates the phosphorylation of NF-kB and JAK/STAT3, according to signalling analyses. Further research using signalling inhibitors and siRNA transfections revealed that the down- and up-regulation of HAS2 and HYBID expression is primarily due to inactivated STAT3 axis signalling caused by activated tyrosine protein phosphatase PTP-Meg2 and activated p38/ATF2 axis signalling, respectively. The ability for Astaxanthin (AX) to abrogate the UVA-suppressed secretion of HA by NHDFs, which is mechanistically connected with its abrogating effects on the reduced expression of HAS2, was discovered during the search for new medicines to treat HA deficiency. Furthermore, we recently discovered that MAAs have a great capacity to induce the secretion of HA by NHDFs, which was accompanied by considerably increased or decreased levels of mRNAs encoding HAS2 and HYBID, respectively. MAAs increase HA secretion by upregulating HAS2 mRNA levels via activation of the intracellular signalling cascade including p38/MSK1/CREB/c-Fos/AP-1, according to our findings. These findings led to the concept that AX and MAAs could be used to treat HA deficit in skin that is chronologically or photo-aged.

Author(s) Details

Genji Imokawa
Center for Bioscience Research & Education, Utsunomiya University, Tochigi, 321-8505 Japan.

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