Annual Report of Cosmetology vol.19, 2011
Synopsis of Original Research Paper

Regulation of hyaluronic acid production via cAMPsignalYoshihiro Ishikawa, Utako Yokoyama
Yokohama City University Graduate School of Medicine

Hyaluronic acid is a kind of mucopolysaccharide and exists abundantly as extracellularmatrix in skin, article, lens and other organs. Skin folding as seen with aging is shown tobe related to a decrease in the content of hyaluronic acid in skin. Supplemental uptake ofhyaluronic acid and addition to cosmetic ointment as well as direct skin injection of hyaluronicacid itself have been commonly employed. Further, in the treatment of article inflammationor lens injury, hyaluronic acid has been used widely in medicine. It has been known that
stimulation of G protein-coupled receptors is necessary to produce hyaluronic acid, leading
to increased cell migration or proliferation. However, the exact molecular mechanism of thissignal transduction in cells has remained undetermined. We have investigated the molecularmechanisms of hyaluronic acid production through cAMP signal in our laboratory. We
have demonstrated that the activation of cAMP signal is essential and resulting increase inhyaluronic acid synthase enzyme expression follows. Because cAMP is produced by adenylylcyclase, a membrane-bound enzyme that is activated by Gs protein, leading to the conversionof ATP to cAMP, it is necessary to investigate the molecular mechanisms of adenylyl cyclase
activation that leads to increased hyaluronic acid production. Adenylyl cyclase enzyme has
many isoforms, from type I to IX, which show distinct tissue distribution and biochemicalproperties. Because the hyaluronic acid production has been best demonstrated in vascularsmooth muscle cells in our laboratory, we examined adenylyl cyclase isoforms that areresponsible for hyaluronic acid production. We also examined the effect of stimulating theseadenylyl cyclase isoforms in an isoform-specific manner using forskolin derivatives thathave increased specificity to these isoforms. We also examined the effect of overexpressing
adenylyl cyclase isoforms in these cells to explore changes in intracellular cell signaling aswell as changes in hyaluronic acid production. Accordingly, we found that specific isoformsof adenylyl cyclase are more responsible for hyaluronic acid production and thus cell
migration thereafter, and that these isoforms play an important role in not only hyaluronic acidproduction, but regulating vascular function such as vasodilatation or endothelial thickening.
Our results have indicated that it is important to understand the role of each adenylyl cyclase
to regulate hyaluronic acid production. Pharmacological stimulation of a specific isoform
of adenylyl cyclase may enable us to enhance the production of hyaluronic acid specifically.
Development of such specific stimulator of adenylyl cyclase may be used in the treatmentof conditions where decrease in hyaluronic content is involved. Indeed, our results havesuggested that such strategy is pharmacologically feasible.
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