Abstract
Background
Skin pigmentation induced by ultraviolet B radiation is caused in part by inflammation
mediated by cytokines secreted from keratinocytes and fibroblasts in the irradiated
area. Heparanase is also activated in the irradiated skin, and this leads to loss
of heparan sulfate at the dermal–epidermal junction (DEJ), resulting in uncontrolled
diffusion of heparan sulfate-binding cytokines through the DEJ. However, it is not
clear whether heparanase-induced loss of heparan sulfate at the DEJ is involved in
the pigmentation process in sun-exposed skin.
Objective
We examined the role of heparan sulfate in the pigmentation process of human pigmented
skin and in pigmented skin-equivalent model.
Methods
Heparan sulfate and blood vessels in human pigmented skin, solar lentigo, and non-pigmented
skin were evaluated by means of immunohistochemistry. Pigmented skin equivalent models
were cultured with or without heparanase inhibitor and the pigmentation levels were
compared.
Results
In solar lentigo, heparan sulfate was hardly observed, presumably due to the increase
of heparanase at the DEJ, in spite of the deposition of core protein of perlecan (also
known as heparan sulfate proteoglycan). The number of blood vessels was significantly
increased in solar lentigo. In the pigmented skin equivalent model, heparanase inhibitor
increased the staining intensity of heparan sulfate at the DEJ and markedly reduced
melanogenesis in the epidermis.
Conclusions
Our results indicate that heparanase-induced loss of heparan sulfate at the DEJ is
involved in the pigmentation process of human skin. Consequently, heparanase inhibitors
can be expected to exert a protective effect against ultraviolet exposure-induced
skin pigmentation.
Abbreviations:
TEWL (transepidermal water loss), UVB (ultraviolet B), DEJ (dermal–epidermal junction), HS (heparan sulfate), SCF (stem cell factor), MSH (melanocyte-stimulating hormone), KGF (keratinocyte growth factor), HGF (hepatocyte growth factor), FGFs (fibroblast growth factors), GM-CSF (granulocyte–macrophage colony-stimulating factor), VEGF-A (vascular endothelial growth factor-A), BIPBIPU (1-[4-(1H-benzoimidazol-2-yl)phenyl]-3-[4-(1H-benzoimidazol-2-yl)phenyl]urea (heparanase inhibitor)), SE (skin equivalent)Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of Dermatological ScienceAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Functional characteristics of the stratum corneum in photoaged skin in comparison with those found in intrinsic aging.Archives of Dermatological Research. 2008; 300: S1-S6
- A gene for freckles maps to chromosome 4q32-q34.Journal of Investigative Dermatology. 2004; 122: 286-290
- Solar lentigines are strongly related to sun exposure in contrast to ephelides.Pigment Cell Research. 2004; 17: 225-229
- Melanin pigmentation in mammalian skin and its hormonal regulation.Physiological Reviews. 2004; 84: 1155-1228
- Regulation of melanogenesis – controversies and new concepts.Experimental Dermatology. 2008; 17: 395-404
- Alterations in the epidermal–dermal melanin axis and factor XIIIa melanophages in senile lentigo and ageing skin.British Journal of Dermatology. 2006; 155: 119-128
- Histopathology of solar lentigines of the face: a quantitative study.Journal of the American Academy of Dermatology. 1997; 36: 444-447
- Gene expression profiling analysis of solar lentigo in relation to immunohistochemical characteristics.British Journal of Dermatology. 2007; 156: 1214-1223
- The role of keratinocyte growth factor in melanogenesis: a possible mechanism for the initiation of solar lentigines.Experimental Dermatology. 2010; 19: 865-872
- Immuno-histochemical evaluation of solar lentigines: the association of KGF/KGFR and other factors with lesion development.Journal of Dermatological Science. 2010; 59: 91-97
- Role of fibroblast-derived growth factors in regulating hyperpigmentation of solar lentigo.British Journal of Dermatology. 2010; 163: 1020-1027
- Morphological changes associated with aging: age spots and the microinflammatory model of skin aging.Annals of the New York Academy of Sciences. 2007; 1119: 32-39
- Heparanase cleavage of perlecan heparan sulfate modulates FGF10 activity during ex vivo submandibular gland branching morphogenesis.Development (Cambridge, England). 2007; 134: 4177-4186
- The binding properties of minimal oligosaccharides reveal a common heparan sulfate/dermatan sulfate-binding site in hepatocyte growth factor/scatter factor that can accommodate a wide variety of sulfation patterns.The Journal of Biological Chemistry. 2009; 284: 6311-6321
- Heparin-binding sites in granulocyte–macrophage colony-stimulating factor. Localization and regulation by histidine ionization.The Journal of Biological Chemistry. 2005; 280: 31949-31956
- Specific structural features of heparan sulfate proteoglycans potentiate neuregulin-1 signaling.The Journal of Biological Chemistry. 2005; 280: 383-388
- Characterization of growth factor-binding structures in heparin/heparan sulfate using an octasaccharide library.The Journal of Biological Chemistry. 2004; 279: 12346-12354
- Specificities of heparan sulphate proteoglycans in developmental processes.Nature. 2000; 404: 725-728
- Involvement of heparan sulfate and related molecules in sequestration and growth promoting activity of fibroblast growth factor.Cancer and Metastasis Reviews. 1996; 15: 177-186
- Heparan sulfate: a complex polymer charged with biological activity.Chemical Reviews. 2005; 105: 2745-2764
- Keratinocyte growth regulation in fibroblast cocultures via a double paracrine mechanism.Journal of Cell Science. 1999; 112: 1843-1853
- Hepatocyte growth factor establishes autocrine and paracrine feedback loops for the protection of skin cells after UV irradiation.The Journal of Investigative Dermatology. 2007; 127: 2637-2644
- Melanosome transfer promoted by keratinocyte growth factor in light and dark skin-derived keratinocytes.The Journal of Investigative Dermatology. 2008; 128: 558-567
- Keratinocyte-derived vascular permeability factor (vascular endothelial growth factor) is a potent mitogen for dermal microvascular endothelial cells.The Journal of Investigative Dermatology. 1995; 105: 44-50
- Metastatic melanoma cell heparanase. Characterization of heparan sulfate degradation fragments produced by B16 melanoma endoglucuronidase.The Journal of Biological Chemistry. 1984; 259: 2283-2290
- Human platelet heparanase: purification, characterization and catalytic activity.Biochemical Journal. 1998; 330: 1341-1350
- Substrate specificity of heparanases from human hepatoma and platelets.The Journal of Biological Chemistry. 1998; 273: 18770-18777
- Heparanase: a key enzyme involved in cell invasion.Biochimica et Biophysica Acta. 2001; 1471: M99-M108
- Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis.Journal of Clinical Investigation. 2001; 108: 341-347
- Purification and characterization of the endoglycosidase heparanase 1 from human plantar stratum corneum: a key enzyme in epidermal physiology?.The Journal of Investigative Dermatology. 2001; 117: 1266-1273
- Heparanase 1: a key participant of inner root sheath differentiation program and hair follicle homeostasis.Experimental Dermatology. 2008; 17: 1017-1023
- Heparanase accelerates wound angiogenesis and wound healing in mouse and rat models.FASEB Journal. 2005; 19: 211-221
- Anti-heparanase monoclonal antibody enhances heparanase enzymatic activity facilitates wound healing.FASEB Journal. 2007; 21: 3986-3993
- Activation of heparanase by ultraviolet B irradiation leads to functional loss of basement membrane at the dermal–epidermal junction in human skin.Archives of Dermatological Research. 2011; 303: 253-261
- 1-[4-(1H-Benzoimidazol-2-yl)-phenyl]-3-[4-(1H-benzoimidazol-2-yl)-phenyl]-urea derivatives as small molecule heparanase inhibitors.Bioorganic & Medicinal Chemistry Letters. 2006; 16: 409-412
- Ultraviolet B irradiation of human skin induces an angiogenic switch that is mediated by upregulation of vascular endothelial growth factor and by downregulation of thrombospondin-1.British Journal of Dermatology. 2005; 152: 115-121
- Reconstituted 3-dimensional human skin of various ethnic origins as an in vitro model for studies of pigmentation.Analytical Biochemistry. 2003; 318: 260-269
- Influence of heparan sulfate chains in proteoglycan at the dermal–epidermal junction on epidermal homeostasis.Experimental Dermatology. 2011; 20: 810-814
- Heparanase activation induces epidermal hyperplasia, angiogenesis, lymphangiogenesis and wrinkles.Experimental Dermatology. 2010; 19: 965-972
- Inhibition of the CXCR3-mediated pathway suppresses ultraviolet B-induced pigmentation and erythema in skin.British Journal of Dermatology. 2010; 163: 593-602
- Heparanase expression in B16 melanoma cells and peripheral blood neutrophils before and after extravasation detected by novel anti-mouse heparanase monoclonal antibodies.Journal of Immunological Methods. 2008; 331: 82-93
- Heparanase degrades syndecan-1 and perlecan heparan sulfate: functional implications for tumor cell invasion.The Journal of Biological Chemistry. 2004; 279: 8047-8055
- Role of leukemia inhibitory factor in the regulation of the proliferation and differentiation of neonatal mouse epidermal melanocytes in culture.Journal of Cellular Physiology. 2002; 192: 315-326
- Steel factor controls the proliferation and differentiation of neonatal mouse epidermal melanocytes in culture.Pigment Cell Research. 2003; 16: 644-655
- Hepatocyte growth factor controls the proliferation of cultured epidermal melanoblasts and melanocytes from newborn mice.Pigment Cell Research. 2004; 17: 51-61
- Granulocyte–macrophage colony-stimulating factor (GM-CSF) controls the proliferation and differentiation of mouse epidermal melanocytes from pigmented spots induced by ultraviolet radiation B.Pigment Cell Research. 2004; 17: 230-240
- Regulation of endothelin-1 and transforming growth factor-beta1 production in cultured proximal tubular cells by albumin and heparan sulphate glycosaminoglycans.Nephrology, Dialysis, Transplantation. 2001; 16: 1769-1775
Iriyama S, Tsunenaga M, Amano S, Adachi E. Key role of heparan-sulfate chains in assembly of anchoring complex at the dermal–epidermal junction. Experimental Dermatology 2011, doi:10.1111/j.1600-0625.2011.01347.x, in press.
Article info
Publication history
Published online: October 17, 2011
Accepted:
September 18,
2011
Received in revised form:
August 31,
2011
Received:
April 18,
2011
Identification
Copyright
© 2011 Japanese Society for Investigative Dermatology. Published by Elsevier Inc. All rights reserved.
