Elucidation of aging mechanism of hyaluronan knock-down mouse and its application to the evaluation for effect of anti-aging reagents

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Hyaluronan(HA), a non-sulfated glycosaminoglycan of high molecular mass, presents in various tissues as a major component of the extracellular matrix and plays an important role in regeneration, wound healing, and anti-aging of organs. We have previously reported that 4-methylumbelliferone(MU) specifically inhibits HA synthesis. In this study, we first investigated the expression of HA-related gene, such as HA synthase(HAS-1, HAS-2, HAS-3), hyaluronidase(Hyal-1, Hyal-2, Hyal-3, Hyal-4), and HA receptor(CD44, RHAMM). We have demonstrated that HAS-2 gene transcription in both epidermis and dermis, and RHAMM transcription in epidermis were reduced in HA-knock-down mice. These data suggested that MU treatment specifically downregulates gene expressions of HAS-2 and RHAMM induced the HA production, resulting in skin aging, such as wrinkle formation and skin dehydration in HA knockdown mice. Next, we have detected sixty one kinds of HA knock-down mice specific genes by using DNA microarray a … More nalysis. Specifically, toll-like receptor 3 gene was strongly down-regulated in HA knock-down mice, suggesting induction of inflammation resulted in skin aging characterize by wrinkle formation. Oncogene expressions such as of tyrosine phosphatase, cyclin Y, and Rho were also down-regulated in HA-knock down mice. Our previous studies have demonstrated MU suppressed the metastasis of malignant tumor cells by inhibiting of HA production. Therefore, these results suggested that down-regulation of these oncogene expression, at least in part, were involved in inhibition of metastasis. On the other hand, gene expression of stromelysin 3, depredating enzyme of extracellular matrix components such as proteoglycan and collagen, strongly up-regulated. These data suggested that the degradation of extracellular matrix resulted in wrinkle formation of HA knock-down mice. Finally, we have administered HA and its oligosaccharides with various molecular weight. As the result, only intradermal injection of high molecular HA decreased skin aging, whereas no change was observed in aged skin by orally or topically administration. Also, skin aging was not reduced by introduction of aging-related gene which was down-regulated in HA knock-down mice, such as COL5A1, COL7A1, RHAMM, toll-like receptor 3, suggesting alone administration of each gene was not effective and cocktail therapy, the combination of multiple genes, was necessary of treatment of skin aging in HA knock-down mice Less