Journal of Dermatological Science

Editorial Board

2010-03-01

CD147/basigin promotes progression of malignant melanoma and other cancers

Takuro Kanekura, Xiang Chen — 2010-03-01

Abstract: CD147/basigin, a transmembrane protein belonging to the immunoglobulin super family, was originally cloned as a carrier of Lewis X carbohydrate antigen. CD147 is strongly related to cancer progression; it is highly expressed by various cancer cells including malignant melanoma (MM) cells and it plays important roles in tumor invasiveness, metastasis, cellular proliferation, and in vascular endothelial growth factor (VEGF) production, tumor cell glycolysis, and multi-drug resistance (MDR). CD147 on cancer cells induces matrix metalloproteinase expression by neighboring fibroblasts, leading to tumor cell invasion. In a nude mouse model of pulmonary metastasis from MM, the metastatic potential of CD147-expressing MM cells injected into the tail vein is abolished by CD147 silencing. CD147 enhances cellular proliferation and VEGF production by MM cells; it promotes tumor cell glycolysis by facilitating lactate transport in combination with monocarboxylate transporters, resulting in tumor progression. CD147 is responsible for the MDR phenotype via P-glycoprotein expression. These findings strongly suggest CD147 as a possible therapeutic target for overcoming metastasis and MDR, major obstacles to the effective treatment of malignant cancers.

Cutaneous consequences of inhibiting EGF receptor signaling in vivo: Normal hair follicle development, but retarded hair cycle induction and inhibition of adipocyte growth in EgfrWa5 mice

2010-03-01

Abstract: Background: The epidermal growth factor receptor (EGFR) network is essential for proper development and homeostasis of skin and hair. However, detailed dissection of the role of the EGFR in hair follicle development and cycling have been impaired by the early mortality of EGFR knockout mice.Objectives: We have studied in Waved-5 mice carrying an antimorphic EGFR allele (Egfrwa5), whose product acts as a dominant-negative receptor, whether strongly reduced EGFR signaling impacts on the hair and skin phenotype.Methods: Histomorphometry and immunohistochemistry were employed to study hair follicle morphogenesis stages and cycle induction in Waved-5 mice and control littermates during embryonic development and postnatal life.Results: By routine histology and quantitative histomorphometry, no significant abnormalities in the epidermis and in hair follicle morphogenesis were detected, while the initiation of hair follicle cycling was slightly, but significantly retarded. Proliferation and apoptosis of epidermal and hair matrix keratinocytes of Waved-5 mice appeared unaltered. Intriguingly, the thickness of the subcutis and the percentage of proliferating subcutaneous adipocytes were significantly reduced in Waved-5 mice around days P8.5 to P10.5. Although no differences in total body weight gain could be detected, Wa5 mice showed a significant reduction in the percentage of body fat at P8.5.Conclusion: Our results suggest the presence of effective compensatory mechanisms in murine skin in vivo that ensure nearly normal epidermal and hair follicle keratinocyte function despite very low levels of EGFR-mediated signaling. Our unexpected findings of transiently reduced subcutaneous adipose tissue indicate a role for the EGFR in regulating subcutaneous fat.

Histological and transcriptional study of angiogenesis and lymphangiogenesis in uninvolved skin, acute pinpoint lesions and established psoriasis plaques: An approach of vascular development chronology in psoriasis

2010-03-01

Abstract: Background: Dysregulation of angiogenesis and lymphangiogenesis could participate in psoriasis pathogenesis. Analysis of nascent psoriasis lesions should help at identifying early vascular anomalies.Objective: To analyse vascular development, angiogenesis and lymphangiogenesis markers expression in uninvolved skin in psoriatic patients (N), early psoriasis lesions or pinpoints (PP) and psoriasis plaques (PSO).Methods: Skin biopsies were taken in 17 patients in N and in PSO and/or PP. The mRNA steady-state level of angiogenesis and lymphangiogenesis markers was measured by RT-PCR. Immunohistochemistry was performed for von Willebrand factor, podoplanin, Ki-67 and VEGFR3. Blood (BV) and lymphatic (LV) vessels expansion was measured by computer-assisted morphometry.Results: Clinical and epidermal aspects indicated that PP are intermediate between N and PSO. While total BV area was already increased in PP similarly to PSO as compared to N, LV area in PP was intermediate between N and PSO. Mean LV size was identical in N and PP and increased in PSO, mean BV size in PP being intermediate between N and PSO. VEGF-A 189 variant was increased in PP as compared to N and PSO. As compared to N, angiogenesis markers (VEGF-A isoforms, PlGF, VEGFR2, NRP-1), VEGF-C and NRP-2 were similarly increased in PP and PSO. Keratin 16 and the lymphangiogenesis markers (VEGFR3, prox-1) were intermediate in PP.Conclusion: These data suggest that the expansion of lymphatic vessels occurs after blood vascular development in psoriasis. Expansion of BV in PP could be followed by vessel enlargement during progression to PSO, in parallel with a decreased VEGF-A 189/VEGF-A 121 balance in plaques.

Inhibition of melanogensis by a novel origanoside from Origanum vulgare

Chia-Hua Liang, Tzung-Han Chou, Hsiou-Yu Ding — 2010-03-01

Abstract: Background: Natural and synthetic substances are becoming increasingly utilized as tyrosinase inhibitors of depigmentation and developed cosmetics industry. However, few have been employed as skin-whitening agents, primarily because of numerous safety concerns.Objective: A novel compound was found, and then its safe concentrations and inhibition effect of hyperpigmentation by the regulation of the tyrosinase family of proteins were examined.Methods: A novel phenolic glucoside, origanoside (1), was isolated from Origanum vulgare. The structure of the origanoside (1) was established on the basis of spectral evidence and the safe concentrations were determined by MTT assay. Skin-whitening capacity in skin fibroblast Hs68 and melanoma B16 cells and in vivo animal test for origanoside (1) were investigated.Results: Origanoside (1) is non-toxic in concentrations of 0–100μg/ml in both cells. The ability of origanoside (1) to inhibit cellular tyrosinase and DOPA oxidase in B16 cells was investigated. Origanoside (1) significantly reduced expressions of microphthalmia-associated transcription factor (MITF), tyrosinase and tyrosinase-related proteins 2 (TRP-2) in vitro and in vivo, suggesting that origanoside (1) is responsible for the antimelanogenic effect. Smearing origanoside (1)-gel samples on 12 mice for 10 days increased L*, reduced a* and erythema-melanin (E/M), and b* was almost unchanged compared with those of samples and untreated groups, indicating that the skin lightened.Conclusion: Experimental data demonstrate that origanoside (1) causes depigmentation and may be useful for novel food additives and skin-whitening cosmetics.

c-Maf and MafB transcription factors are differentially expressed in Huxley's and Henle's layers of the inner root sheath of the hair follicle and regulate cuticle formation

2010-03-01

Abstract: Background: The hair follicle of mammalian skin consists of a group of concentric epithelial cell layers. The inner root sheath (IRS), which surrounds the hardening hair shaft beneath the skin surface, is subdivided into three layers, termed the cuticle of the IRS, Huxley's layer, and Henle's layer. The IRS forms a follicular wall in the hair canal and helps guide the developing hair shaft. c-Maf and MafB, members of the Maf family of transcription factors, play important roles in the developmental processes of various tissues and in cell type-specific gene expression.Objective: The aim of this study is to reveal the pattern of expression and functional roles of c-Maf and MafB in the hair follicle.Methods: We determined the precise location of c-Maf and MafB expression using immunofluorescent staining of mouse skin sections with layer-specific markers. We also analyzed whiskers of c-maf- and mafB-null mice (c-maf−/− and mafB−/−, respectively) using scanning electron microscopy.Results: c-Maf and MafB were differentially expressed in the Huxley's and Henle's layers of the IRS. Scanning electron microscopic analysis showed irregular cuticle patterning of whiskers of c-maf−/− and mafB−/− mice. The cuticles of mafB−/− mice were also thinner than those of wild-type mice.Conclusion: c-Maf and MafB are expressed in the IRS layers in a lineage-restricted manner and are involved in hair morphogenesis.

Topical application of anti-angiogenic peptides based on pigment epithelium-derived factor can improve psoriasis

2010-03-01

Abstract: Background: Psoriasis is a common chronic inflammatory skin disorder with a high prevalence (3–5%) in the Caucasian population. Although the number of capillary vessels increases in psoriatic lesions, there have been few reports that have specifically examined the role of angiogenesis in psoriasis. Angiogenic factors, such as vascular endothelial growth factor (VEGF), may dominate the activity of anti-angiogenic factors and accelerate angiogenesis in psoriatic skin.Objective: We investigated to identify small peptide mimetics of PEDF that might show anti-angiogenic potential for the topical treatment for psoriasis.Methods: We examined the expression of PEDF in skin by immunohistochemical staining, immunoblotting, and RT-PCR. To identify potential PEDF peptides, we screened peptides derived from the proteolytic fragmentation of PEDF for their anti-proliferative action. Anti-psoriatic functions of these peptides were analyzed using a mouse graft model of psoriasis.Results: The specific low-molecular weight peptides (MW<850Da) penetrated the skin and showed significant anti-angiogenic activity in vitro. Topical application of these peptides in a severe combined immunodeficient mouse model of psoriatic disease led to reduced angiogenesis and epidermal thickness.Conclusions: These data suggest that low-molecular PEDF peptides with anti-angiogenic activity may be a novel therapeutic strategy for psoriasis.

Bidimensional analysis of desmoglein 1 distribution on the outermost corneocytes provides the structural and functional information of the stratum corneum

Yoshikazu Naoe, Tsuyoshi Hata, Koko Tanigawa, Hiroko Kimura, Takuji Masunaga — 2010-03-01

Abstract: Background: The stratum corneum (SC) plays an important role in cutaneous barrier function. Recent clarification of the pathophysiology of several keratoses has suggested that adhesive molecules contribute not only to SC construction but also to SC barrier function.Objective: The purpose of this study is to clarify how the distribution of adhesion molecules on corneocytes contributes to the construction of the SC and the overall organization and function of the cutaneous barrier.Methods: To investigate the distribution of desmoglein 1 (Dsg1), which may be a main component of corneodesmosomes (CDSs) in the SC, we used a bidimensional observation method using tape-stripped corneocytes and several immunohistochemical techniques to demonstrate the distribution of Dsg1 and to deduce internal events in the SC.Results: Immunofluorescence labeling showed that Dsg1 distributed on corneocytes of the outermost SC with a characteristic pattern at the periphery, or over the entire surface, and differences in this distribution pattern correlated with the transepidermal water loss (TEWL). Furthermore, electron microscopic analysis showed that (1) Dsg1 was localized on CDSs involved in adhesion, and (2) CDSs on the periphery of corneocytes contributed to the generation of the characteristic basket-weave structure.Conclusion: We explored the distribution pattern of Dsg1 in the SC via a non-invasive investigation tool. Our findings indicate the significance of adhesion molecules in the formation and function of the SC, and suggest that adhesion molecules are one of the important elements in barrier formation in addition to corneocytes, which act as bricks, and intercellular lipids, which act as mortar.

Association of single nucleotide polymorphisms in the IL-12 (IL-12A and B) and IL-12 receptor (IL-12Rβ1 and β2) genes and gene–gene interactions with atopic dermatitis in Koreans

2010-03-01

Abstract: Background: The acute skin lesions of atopic dermatitis (AD) are associated with Th2 cells; however, the chronic skin lesions of AD are associated with Th1 cells via the action of IL-12.Objective: We evaluated the associations of single nucleotide polymorphisms (SNPs) and haplotype in the IL-12 and IL-12 receptor genes, and determined the gene–gene interactions between the SNPs of these genes and the SNPs of the IL-18 gene that we previously reported.Method: We genotyped 24 SNPs from 4 IL-12/IL-12R genes for 1089 case–control samples (631 AD patients and 458 normal controls). We measured the serum IL-12 concentrations in 89 individuals (79 AD patients and 10 controls) by ELISA. We analyzed the SNPs and haplotypes in each gene and also searched for the gene–gene interactions.Result: The rs582504 (IVS−798A/T) SNP and the haplotype TA (rs582054 and rs2243151) in the IL-12A gene, and the rs438421 (IVS12+1266T/C) SNP and the haplotype CCA (rs375947, rs438421, and rs1870063) in the IL-12RB1 gene were significantly associated with the AD phenotype. We showed that the rs438421 polymorphism in the IL-12RB1 (TT) gene and the rs2066446 polymorphism in the IL-12RB2 (AA) gene had a significant interaction to develop the ADe phenotype (allergic type of AD), and those individuals with the risk alleles, TT/AA/CC (IL-12RB1/IL-12RB2/IL-18), have more than a 10-fold increased risk to develop ADe.Conclusion: This study provides evidence for a significant interaction between the IL-12RB1 and IL-12RB2 genes that contribute to a 4-fold increased risk for developing ADe. In addition to the IL-12R interaction, we suggest that the IL-18 gene can significantly interact with the IL-12R gene to develop ADe. In addition to the interaction, the SNPs and haplotypes in the IL-12A and IL-12RB1 genes are independently and significantly associated with the AD phenotype, and especially with the ADe phenotype. This data may contribute to our understanding of AD genetic interactions and account for the additional risk of certain patients to develop AD.

Keratinocyte differentiation induced by calcium, phorbol ester or interferon-γ elicits distinct changes in the retinoid signalling pathways

Teresa Karlsson, Anders Vahlquist, Hans Törmä — 2010-03-01

Abstract: Background: Retinoids influence keratinocyte proliferation and differentiation via binding to nuclear retinoic acid receptors (RARα, -γ) and retinoid X receptor α (RXRα). The effect of keratinocyte differentiation on expression of nuclear retinoid receptors and on the conversion of retinol into retinoic acid has not been examined earlier in depth.Objectives: Our aim was to examine the expression of retinoid receptors and a retinoid-regulated gene CRABPII, as well as the metabolism of exogenous [3H]retinol in cultured human keratinocytes induced to differentiate by exposure to either calcium, phorbol 12-myristate 13-acetate (PMA), or interferon-γ (IFNγ).Methods: Normal human keratinocytes were cultured and exposed to differentiation-inducing agents. The mRNA and protein expression of retinoid receptors were examined using real-time PCR and Western blot. [3H]Retinol uptake and metabolism was monitored by HPLC with on-line radioactivity detection.Results: In calcium-exposed cells, increased expression of RARγ and RXRα, enhanced metabolism of [3H]retinol to 3,4-didehydro-RA (ddRA), and an induction of CRABPII mRNA and protein was noted. In contrast, treatment with PMA and IFNγ reduced the RARγ and RXRα protein expression (preventable by the proteasome inhibitor MG132), increased the accumulation of [3H]RA and/or [3H]ddRA in the cells, and changed the CRABPII transcription.Conclusions: Retinoid signalling is profoundly altered upon differentiation of keratinocytes and the effects depend on how cellular differentiation is initiated.

Follow up study of dermal hyaluronic acid injection by high frequency ultrasound and magnetic resonance imaging

G. Josse, M. Haftek, D. Gensanne, V. Turlier, A. Mas, J.M. Lagarde, A.M. Schmitt — 2010-03-01

In the last few years, increasing use of injectable resorbable fillings has been reported for facial wrinkle treatment and for soft tissue augmentation of HIV-associated facial lipodystrophy . However, important practical information concerning the localization and subsequent diffusion of the injected product in skin tissues are poorly documented. Histological analysis has been previously used to compare different kinds of fillers , to evaluate remanescence of the injected material , or to observe the product placement at the injection site . Wang et al. have recently proposed a mechanism in which the filler-induced mechanical tension solicits local fibroblasts and activates collagen synthesis .

Characterization of dendritic cells and macrophages in irritant contact dermatitis

H. Tang, C. Schlapbach, A.S. Hassan, D. Simon, N. Yawalkar — 2010-03-01

Irritant contact dermatitis (ICD) is a non-allergic inflammatory reaction of the skin caused by direct cytotoxic effects of irritant chemicals or physical agents. It is one of the most common cutaneous diseases . In the past, the pathogenesis of ICD was thought to be non-immunological while allergic contact dermatitis (ACD) was presumed immune mediated. Today, it has become increasingly accepted that the immune systems plays an important part in eliciting ICD . The current concept of ICD pathogenesis is that irritants cause disruption of skin barrier function and damage to keratinocytes. Consequently, a local inflammatory response is mounted .

The papillary structure identified by a novel nail wound healing model in mice

2010-03-01

The nails are located at the dorsal aspect of the fingers and toes . The function of nails is to protect, resist pressure on the digits, and detect certain sensations . Since nails are located at the periphery of the body, they are easily damaged or shed by external stimuli . Since nails play important role in the distal extremities, rapid healing of the damaged nail is desirable .

Announcements

2010-03-01