The retinoic acid-induced up-regulation of insulin-like growth factor 1 and 2 is associated with prolidase-dependent collagen synthesis in UVA-irradiated human dermal equivalents

BackgroundUltraviolet (UV) A irradiation causes the degeneration of extracellular matrix in the skin dermis, mainly due to disrupted collagen homeostasis, resulting in the photo-aging of human skin. All-trans retinoic acid (ATRA) improves photo-aged human skin in vivo.ObjectivesAlthough the effects of ATRA on collagen synthesis and MMP regulation are well known, the effects of ATRA on other collagen homeostasis-associated genes have not been elucidated. This study was aimed to study the factors that are pharmacologically associated with the effect of ATRA on collagen homeostasis.MethodsThe gene transcription profile of collagen homeostasis-associated genes was systematically evaluated in three-dimensional human dermal equivalents (HDEs) following UVA-irradiation and/or ATRA treatment.ResultsIn addition to the expected changes in MMPs and collagen synthesis in HDEs in response to ATRA, prolidase, an important enzyme in the recycling of proline and hydroxyproline from degraded collagen molecules, was significantly decreased by UVA irradiation, and its down-regulation was antagonized by ATRA. Transfection with a prolidase-specific siRNA led to a significant decrease in procollagen synthesis in human fibroblasts. ATRA inhibited the UVA irradiation-induced decrease in prolidase activity through an insulin-like growth factor (IGF) receptor signaling pathway in HDEs. ARTA increased IGF1 and IGF2 production in HDEs, and neutralizing IGFs with anti-IGF antibodies abolished the effect of ATRA on proliase activity.ConclusionsThese data demonstrate that ATRA regulates prolidase activity in HDEs via IGF receptor signaling, suggesting one of the pharmacological mechanisms by which improves photo-aged human skin.