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In most mammalian species, VC is synthesized in the liver. However, some species, such as primates and guinea pigs, are unable to synthesize VC because of mutations in the gene encoding gulono-gamma-lactone oxidase (GLO) [8]. VC deficiency induces skin disorders such as delayed wound healing or impaired collagen synthesis in vivo [9] and [10]. It is well known that VC is required for post-translational proline hydroxylation of collagen molecules [11] and hydroxyproline residues play a critical role in stabilizing the triple helical structure of the collagen [12]. Transcriptional activation of type I collagen Nutlin-3 by VC or its derivative was also reported in cultured human skin fibroblasts [13] and [14]. Furthermore, VC is thought to be involved in the regulation of keratinocyte function as an anti-oxidant [15].
Materials and methods
Animals. The SMP30 KO mice were previously generated with the gene-targeting technique [5]. Heterozygous female mice (SMP30 +/?) were mated with male KO mice (SMP30 Y/?) to produce SMP30 KO (SMP30 Y/?) and WT (SMP30 Y/+) littermates. The mice were weaned at day 34 of age, and fed a VC-deficient diet (CL-2; CLEA Japan, Tokyo) for 36 days. Other groups of animals were weaned between days 28 and 35 of age, and fed the VC-deficient diet for 60 days. During the periods, the mice were given water containing either VC (l-ascorbic acid, 1.5 g/L) or hydrochloric acid (HCl, pH 3.0). The VC water also contained 10 μM ethylenediaminetetraacetic acid (EDTA) for stabilizing VC. The food and water were available ad libitum. Throughout the experiments, animals were maintained on 12-h light dark cycles in a controlled environment. All experimental procedures using laboratory animals were approved by the Animal Care and Use Committee of Tokyo Metropolitan Institute of Gerontology.