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

Abstract

Hyaluronan (HA) is an extracellular matrix glycosaminoglycan that is physiologically enriched in the dermis and critically supports the physicochemical and mechanical properties of the skin. Little is known about the cellular mechanism(s) underlying the age-dependent deficiency of HA in the dermis of aged skin. We first examined the effects of chronological aging and ultraviolet (UV) A irradiation on the secretion of HA by human dermal fibroblasts (NHDFs) and characterized the cellular and intracellular signaling mechanisms that regulate its synthesis and degradation by enzymes including HA synthases (HAS), hyaluronidases (HYAL) and HYaluronan Binding protein Involved in HA Depolymerization (HYBID). Those results indicate that the age-dependent deficiency of HA in the dermis results from an age-dependent down-regulation in the potential of NHDFs to secrete HA and that decrease in secretion is mainly associated with the down-regulated expression of HASs, especially HAS2. On the other hand, the secretion of HA by NHDFs was found to be suppressed by UVA radiation, accompanied by the down- and up-regulation of mRNA and protein levels of HAS2 and the HA-degrading protein, HYBID, respectively. Signaling analysis revealed that UVA exposure distinctly elicits activation of 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. Further analyses using signaling inhibitors and siRNA transfections revealed that the down- and up-regulation of HAS2 and HYBID expression are mainly ascribed to inactivated signaling of the STAT3 axis due to the activated tyrosine protein phosphatase PTP-Meg2 and the activated signaling of the p38/ATF2 axis, respectively. Screening for prospective agents to ameliorate the HA deficiency revealed that Astaxanthin (AX) has the potential to abrogate the UVA-suppressed secretion of HA by NHDFs, which is mechanistically associated with its abrogating effects on the decreased expression of HAS2. In addition, we recently found that mycosporine-like amino acids (MAAs) have a significant potential to stimulate the secretion of HA by NHDFs which was accompanied by significantly increased or decreased levels of mRNAs encoding HAS2 and HYBID, respectively. Our signaling analyses revealed that MAAs stimulate HA secretion by up-regulating HAS2 mRNA levels through activation of the intracellular signaling cascade consisting of p38/MSK1/CREB/c-Fos/AP-1. These findings lead to the hypothesis that AX and MAAs can serve as prospective agents to ameliorate the deficiency of HA in chronologically or photo- aged skin.