The role of keratinocyte growth factor in melanogenesis: a possible mechanism for the initiation of solar lentigines.
ABSTRACT Solar lentigines (SLs) are hyperpigmentary lesions presented on sun-exposed areas of the skin and associated with ageing. The molecular mechanism of SL initiation is not completely understood. Ultraviolet B (UVB) stimulates keratinocytes to produce interlukin-1 alpha (IL-1α), which then induces keratinocyte growth factor (KGF) secretion; therefore, we examined their possible roles in the induction of SLs. We found that KGF increases pigment production in both pigmented epidermal equivalents and human skin explants. In addition, UVB exposure increases KGF expression, and KGF treatment induces tyrosinase (TYR) expression in primary melanocytes. The KGF-induced pigmentary changes were confirmed using pigmented Yucatan swine, and human skins grafted onto immuno-deficient mice. In both model systems, the topical treatment with KGF, alone or in combination with IL-1α, resulted in the in vivo formation of hyperpigmentary lesions with increased pigment deposition and elongated rete ridges, which resemble the histological features of human SLs. Preliminary immunohistochemical analysis of human skins showed a moderate increase in KGF, and a strong induction in KGF receptor (KGFR) in SL lesions. In summary, KGF increases pigment production and deposition in vitro and in vivo. Moreover, we show for the first time the in vivo generation of hyperpigmentary lesions with histological resemblance to human SLs and indicate the involvement of KGF/KGFR in the molecular pathology of human SLs.
- SourceAvailable from: Tomohisa Hirobe[Show abstract] [Hide abstract]
ABSTRACT: BACKGROUND: Although keratinocyte-derived factors are known to promote the proliferation and differentiation of human epidermal melanocytes, it is not fully understood whether fibroblast-derived factors work in a similar way. OBJECTIVE: The aim of this study is to clarify whether fibroblast-derived factors are involved in regulating the proliferation and differentiation of human melanocytes with or without keratinocytes using serum-free culture system. METHODS: Human epidermal melanoblasts and melanocytes were cultured in a serum-free growth medium supplemented with fibroblast-derived factors such as keratinocyte growth factor (KGF) with or without keratinocytes, and the effects of KGF on the proliferation and differentiation of melanocytes were studied. RESULTS: KGF stimulated the proliferation of melanoblasts in the presence of dibutyryl cAMP (DBcAMP), basic fibroblast growth factor (bFGF), transferrin (Tf), and endothelin-1 (ET-1). Although KGF stimulated the differentiation, melanogenesis, and dendritogenesis in the presence of DBcAMP, Tf, and ET-1 without keratinocytes, KGF required the presence of keratinocytes for the stimulation of melanocyte proliferation. CONCLUSION: These results suggest that fibroblast-derived KGF stimulates the proliferation of human melanoblasts in synergy with cAMP, bFGF, Tf, and ET-1, the differentiation of melanocytes in synergy with cAMP, Tf, and ET-1, and the proliferation of melanocytes in synergy with cAMP, Tf, ET-1, and undefined keratinocyte-derived factors.Journal of dermatological science 04/2013; DOI:10.1016/j.jdermsci.2013.03.012 · 3.34 Impact Factor
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ABSTRACT: Solar lentigines (SLs) are macular hyperpigmented lesions associated with sun exposure and age. Histopathologically, SLs are defined by a hyperpigmented basal layer and elongated rete ridges. The molecular mechanisms involved in the formation and the development of SLs are not completely understood. Our earlier data show that keratinocyte growth factor (KGF) induces hyperpigmentary lesions with histological resemblance to SLs. To investigate the association of KGF/KGF receptor (KGFR) and other pigmentary genes with the progression of SL development. To better understand the possible role of KGF in the pathology of SLs. Archived human skin biopsies (24 SLs and 14 healthy skins) were studied using immunohistochemistry for KGF/KGFR, proliferation marker Ki67, stem cell marker keratin-15 (K15), tyrosinase (TYR), stem cell factor (SCF), and protease-activated receptor-2 (PAR-2). An increase in TYR-positive cells and expression was found throughout SL progression, as compared to normal skin. The levels of KGF, KGFR, SCF, Ki67 and PAR-2 varied during SL progression. Ki67, K15 and KGF/KGFR were significantly upregulated at early-mid SL stages. The latest-stage SLs expressed the lowest levels of KGF, KGFR, SCF, Ki67 and PAR-2. The upregulation of KGF/KGFR might induce the formation of rete ridges and hyperpigmentation. The reduced levels of all examined proteins (except TYR and K15) suggest a possible inactive status (dormancy or quiescence) of advanced lesions.Journal of dermatological science 08/2010; 59(2):91-7. DOI:10.1016/j.jdermsci.2010.06.006 · 3.34 Impact Factor
Article: Photoprotection et maladies cutanées[Show abstract] [Hide abstract]
ABSTRACT: Excessive exposure to solar or artificial sources of UV radiation is deleterious to the skin and can cause or worsen several diseases. Detrimental effects of UV radiation exert an important role in the development of skin cancers, cause alterations on the immune response, and act as a trigger or aggravating factor for pigmentary disorders. A group of measures, including education, change of habits, use of physical barriers and sunscreens constitutes a significant part of the treatment of many skin disorders and are valuable preventive tools. This article summarizes the relevant studies addressing these issues, emphasizing the many aspects of photoprotection.Annales de Dermatologie et de Vénéréologie 11/2012; 139:S83–S91. DOI:10.1016/S0151-9638(12)70116-3 · 0.67 Impact Factor