Abstract
Most organisms have adapted to the diurnal cycle with the circadian clock. Circadian clock is an endogenous timing mechanism that allows the anticipation of daily changes and the operation of biological functions. The skin is subjected to daily variation in environments, and its circadian clock system responses to daily changes, thereby regulating skin functions. Acute and chronic exposure of the skin to UV irradiation causes the extensive disruption of dermal connective tissue and DNA damage, and ultimately leads premature skin aging (photoaging) and skin cancer. It is previously reported that both DNA repair, which is a mechanism for removing UV photoproducts, and DNA replication are regulated by the circadian clock in mouse skin. However, a molecular link between the circadian clock and dermal connective tissue has not been investigated. Interestingly, we observed the PERIOD protein, a morning clock component, represses the expression of matrix metalloproteinase-1 (MMP-1) by using a PER-knockdown strategy in human keratinocytes. Also, treatment of siPer3 alleviated the suppression of MMP1 expression by forskolin, an inducer of cAMP signaling, which activates the Per gene expression. These results revealed that PER3 suppresses MMP1 expression via cAMP signaling pathway. Additionally, we screened a regulator of skin circadian clock gene using the HaCaT cell line containing Per-luciferase reporter gene to find an inhibitor of MMP1. The results showed that Lespedeza capitata extract increases Per activity in dose-dependent manner without cell proliferation or cytotoxicity. Also, L. capitata extract inhibits MMP1 expression and its effect abolished in HaCaT transfected siPer3. The results showed that L. capitata extract regulated MMP1 expression through PER3. Based on our study, we suggest that circadian clock gene PER regulates dermal connective tissues and may be a useful molecular target for alleviating the skin aging and skin cancer.
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