Yorihisa Kotobuki

Periostin, a matricellular protein, accelerates cutaneous wound repair by activating dermal fibroblasts

Abstract:  Cutaneous wound repair is a highly ordered and well‐coordinated process involving various cell lineages and many molecular effectors. Cell–matrix interactions through integrin molecules provide key signals important for wound repair. Periostin is a matricellular protein that may provide signals important during tissue development and remodelling by interacting with several integrin molecules, via the phosphatidylinositol 3‐kinase/Akt and MAP kinase pathways. In this study, we examined the role of periostin in the process of cutaneous wound repair using periostin‐deficient mice and by analysing the effects of periostin on dermal fibroblasts. We first determined the expression profile and localization of periostin in a well‐characterized wound repair model mice. Periostin was robustly deposited in the granulation tissues beneath the extended epidermal wound edges and at the dermal–epidermal junctions in wounded mice. Moreover, periostin‐deficient mice exhibited delayed in vivo wound repair, which could be improved by direct administration of exogenous periostin. In vitro analyses revealed that loss of periostin impaired proliferation and migration of dermal fibroblasts, but exogenous supplementation or enforced periostin expression enhanced their proliferation. Combined, these results demonstrate that periostin accelerates the process of cutaneous wound repair by activating fibroblasts.

Dysregulation of melanocyte function by Th17‐related cytokines: significance of Th17 cell infiltration in autoimmune vitiligo vulgaris

The aim of this study was to determine whether CD4+IL‐17A+Th17 cells infiltrate vitiligo skin and to investigate whether the proinflammatory cytokines related to Th17 cell influence melanocyte enzymatic activity and cell fate. An immunohistochemical analysis showed Th17 cell infiltration in 21 of 23 vitiligo skin samples in addition to CD8+ cells on the reticular dermis. An in vitro analysis showed that the expression of MITF and downstream genes was downregulated in melanocytes by treatment with interleukin (IL)‐17A, IL‐1β, IL‐6, and tumor necrosis factor (TNF)‐α. Treatment with these cytokines also induced morphological shrinking in melanocytes, resulting in decreased melanin production. In terms of local cytokine network in the skin, IL‐17A dramatically induced IL‐1β, IL‐6, and TNF‐α production in skin‐resident cells such as keratinocytes and fibroblasts. Our results provide evidence of the influence of a complex Th17 cell‐related cytokine environment in local depigmentation in addition to CD8+ cell‐mediated melanocyte destruction in autoimmune vitiligo.

Periostin Facilitates Skin Sclerosis via PI3K/Akt Dependent Mechanism in a Mouse Model of Scleroderma

Objective Periostin, a novel matricellular protein, is recently reported to play a crucial role in tissue remodeling and is highly expressed under fibrotic conditions. This study was undertaken to assess the role of periostin in scleroderma. Methods Using skin from patients and healthy donors, the expression of periostin was assessed by immunohistochemistry and immunoblotting analyses. Furthermore, we investigated periostin−/− (PN−/−) and wild-type (WT) mice to elucidate the role of periostin in scleroderma. To induce murine cutaneous sclerosis, mice were subcutaneously injected with bleomycin, while untreated control groups were injected with phosphate-buffered saline. Bleomycin-induced fibrotic changes were compared in PN−/− and WT mice by histological analysis as well as by measurements of profibrotic cytokine and extracellular matrix protein expression levels in vivo and in vitro. To determine the downstream pathway involved in periostin signaling, receptor neutralizing antibody and signal transduction inhibitors were used in vitro. Results Elevated expression of periostin was observed in the lesional skin of patients with scleroderma compared with healthy donors. Although WT mice showed marked cutaneous sclerosis with increased expression of periostin and increased numbers of myofibroblasts after bleomycin treatment, PN−/− mice showed resistance to these changes. In vitro, dermal fibroblasts from PN−/− mice showed reduced transcript expression of alpha smooth actin and procollagen type-I alpha 1 (Col1α1) induced by transforming growth factor beta 1 (TGFβ1). Furthermore, recombinant mouse periostin directly induced Col1α1 expression in vitro, and this effect was inhibited by blocking the αv integrin-mediated PI3K/Akt signaling either with anti-αv functional blocking antibody or with the PI3K/Akt kinase inhibitor LY294002. Conclusion Periostin plays an essential role in the pathogenesis of Bleomycin-induced scleroderma in mice. Periostin may represent a potential therapeutic target for human scleroderma.

Impact of sedative and non-sedative antihistamines on the impaired productivity and quality of life in patients with pruritic skin diseases.

BACKGROUND The impairment that pruritic skin diseases have on patient productivity at work, in the classroom, and in daily activities is substantial and needs to be characterized. The objective of this study was to determine how pruritic skin diseases impact patient productivity and quality of life (QOL), in order to improve the measurement of these endpoints to allow the influence of treatment options including sedative and non-sedative antihistamines to be analyzed. METHODS The impact of pruritic skin diseases and the effect of antihistamine therapy on work, classroom, and daily productivity were evaluated using the Work Productivity Assessment Index-Allergy Specific Questionnaire. The intensity of itch and patient QOL were assessed using a visual analogue scale and Skindex-16, respectively. RESULTS Pruritic skin diseases resulted in significant impairment of work, classroom, and daily productivity. The severity of overall work impairment in atopic dermatitis (AD), urticaria, and prurigo was higher than for other diseases analyzed. However, classroom activity was more adversely affected in patients with urticaria relative to other diseases. All pruritic diseases in this study negatively impacted daily activity to a similar degree. Impaired productivity was significantly improved in patients taking non-sedative antihistamines for 1 month, and the improvements correlated with the alleviation of itch and improved QOL. CONCLUSIONS These results indicate that pruritic skin diseases reduce patient productivity at work, in the classroom, and during daily activities, and that non-sedative antihistamines may offer an advantage over sedative antihistamines for alleviating certain negative consequences of these skin diseases.

Periostin accelerates human malignant melanoma progression by modifying the melanoma microenvironment

Given no reliable therapy for advanced malignant melanoma, it is important to elucidate the molecular mechanisms underlying the disease progression. Using a quantitative proteomics approach, the ‘isobaric tags for relative and absolute quantitation (iTRAQ)’ method, we identified that the extracellular matrix protein, periostin (POSTN), was highly expressed in invasive melanoma compared with normal skin. An immunohistochemical analysis showed that POSTN was expressed in all invasive melanoma (n = 20) and metastatic lymph node (n = 5) tissue samples, notably restricted in their stroma. In terms of the intercellular regulation of POSTN, we found that there was upregulation of POSTN when melanoma cells and normal human dermal fibroblasts (NHDFs) were cocultured, with restricted expression of TGF‐β1 and TGF‐β3. In a functional analyses, recombinant and NHDF‐derived POSTN significantly accelerated melanoma cell proliferation via the integrin/mitogen‐activated protein kinase (MAPK) signaling pathway in vitro. The size of implanted melanoma tumors was significantly suppressed in POSTN/Rag2 double knockout mice compared with Rag2 knock‐out mice. These results indicate that NHDF‐derived POSTN accelerates melanoma progression and might be a promising therapeutic target for malignant melanoma.

New aspect of anti-inflammatory action of lipo-prostaglandinE1 in the management of collagen diseases-related skin ulcer.

It is considered that the mechanism in intractable cutaneous ulcer is deeply associated with prolongation at the inflammatory phase. Having evaluated the effects of Lipo-prostaglandin E1 (Lipo-PGE1) with indicators such as the reduction ratio of the ulcer area and the values of the inflammatory markers after dividing them into two groups of collagen diseases and non-collagen diseases and giving them Lipo-PGE1, we managed to obtain the result that Lipo-PGE1 administration could influence various inflammatory markers such as C-reactive protein (CRP), IL-6, and VEGF in addition to reduction of the ulcer region. It also suggested that Lipo-PGE1 has the effect of maintaining an appropriate balance of induction of inflammation and angiogenesis. Additionally, it revealed that Lipo-PGE1 controls the production of cytokines, which are associated with the growth of collagen diseases. From these results, it can be expected that Lipo-PGE1 will act favorably on intractable collagen diseases.

Cutaneous symptoms in a patient with cardiofaciocutaneous syndrome and increased ERK phosphorylation in skin fibroblasts

completion of treatment the contacts of the patients with their doctor will diminish, while the information need of the melanoma survivor may still exist. Patients diagnosed and treated shortly before the completion of the questionnaire might have a clearer picture of the information they received and therefore reported to have received more information. Younger and more highly educated melanoma patients are more likely to be actively involved in decision-making processes and ask more questions. Older patients are reported to be less interested in detailed information and leave the provision of details up to the doctor. Likewise, doctors can be prejudiced against older patients. Furthermore, older and less educated patients may have more difficulties processing and remembering information they receive and may compensate for their reduced cognitive capacity by asking fewer questions to their specialist. The observed variation in information satisfaction levels between patients treated in different hospitals can be explained by the variation in patient-centred information provision, which is strongly related to information recall and understanding. Our finding that only 25% of the melanoma survivors wanted more information could be explained by the increasing internet use of melanoma patients. When patients are not satisfied with the information received from their health care provider, they will search for additional information on the internet. Health care providers often have limited time and resources to provide the information that melanoma patients require. With growing evidence that well-informed patients are more satisfied with their care, and do better clinically, efforts are needed to improve the information provision to melanoma patients. Exploration of the patients’ personal information needs must lead to a more patient-tailored approach of informing melanoma patients. A good opportunity would be the implementation of a survivorship care plan, which aims at providing a cancer survivor with a summary of their course of treatment, management of late effects, and strategies for health promotion.

Seven cases of vitiligo complicated by atopic dermatitis: suggestive new spectrum of autoimmune vitiligo.

ejd.2012.1656 Auteur(s) : Atsushi Tanemura1 tanemura@derma.med.osaka-u.ac.jp, Tomoko Yajima1, Mayuko Nakano1, Megumi Nishioka1, Saori Itoi1, Yorihisa Kotobuki1, Mari Higashiyama2, Ichiro Katayama1 1 Department of Dermatology, Osaka University School of Medicine, 2-2 Yamadaoka Suita, Osaka 565-0871, Japan 2 Department of Dermatology, Nissei Hospital, Osaka, Japan A recent report strongly suggests that genetic polymorphisms such as the NALP1 gene are closely associated with generalized vitiligo, especially [...]

Role of macrophage infiltration in successful repigmentation in a new periphery-spreading vitiligo lesion in a male Japanese patient

Vitiligo is an acquired disorder in which depigmented macules result from mostly autoimmune loss of melanocytes. The initiating process in vitiligo has still been uncertain. Here, we report the case of a 19‐year‐old man with undetermined/unclassified vitiligo with a new periphery‐spreading vitiligo lesion on the right dorsal hand after rigorous sun exposure. Histopathological evaluation showed noticeable infiltration of CD68+ macrophages, moderate infiltration of CD3+ T cells, little infiltration of CD8+ T cells and CD11c+ myeloid dendritic cells, HMB45/CD11c double‐positive cells, and Melan‐A/MART1+ deposits in the dermis. We surmised that melanocyte‐derived deposits were mostly phagocytosed by CD68+ macrophages and were faintly phagocytosed by CD11c+ myeloid dendritic cells, referring distribution of CD68+ mononuclear cells and melanocyte biomarkers. Complete repigmentation was achieved following topical application of hydrocortisone butyrate propionate 0.1% ointment. We summarize that prompt clearance of debris by macrophages would be essential to an excellent prognosis of complete repigmentation.

OP0230 Periostin, a novel matricellular protein, is required for cutaneous sclerosis in a mouse model of scleroderma

Background Scleroderma impairs patients’ quality of life and frequently threatens patients’ lives. There is still no established treatment for the fibrosis in scleroderma.Elucidation of the underlying cause of this disease has been much awaited. Recently, the matricellular molecules and their associated molecules in skin were suggested to play key roles in scleroderma, and the studies on them are still on-going. Objectives Periostin, a novel matricellular protein, is recently reported to paly a crucial role in tissue remodeling, and highly expressed in fibrotic conditions. This study was undertaken to assess the role of periostin in scleroderma. Methods Using patients and healthy donors’ skin tissues, expression of periostin was assessed by immunohistochemistry and immunoblotting analysis. Furthermore, we investigated periostin-/- (PN-/-) mice and wild-type (WT) mice to elucidate the role of periostin in scleroderma. To induce murine cutaneous sclerosis, mice were subcutaneously injected with bleomycin, while untreated control groups were injected with phosphate buffered saline. Bleomycin-induced fibrotic changes were compared between PN-/-and WT mice, by histologic analysis, as well as measuring profibrotic cytokines and extracellular matrix proteins (ECM) expression in vivo and in vitro. To determine the downstream signal transduction pathway for the effect of exogenous periostin, signal-transduction inhibitors were used in vitro. Results Elevated expression of periostin was observed in lesional skin of patients with scleroderma, compared with healthy donors. Regarding the animal experiments, although WT mice showed marked cutaneous sclerosis with increased expression of periostin and increased number of myofibroblasts by bleomycin treatment, PN-/- mice showed resistant to these changes. In vitro, PN-/- mice dermal fibroblasts showed reduced transcripts expression of transforming growth factor beta 1 (TGFβ1)-induced alpha smooth muscle actin (αSMA) and procollagen type I alpha 1 (Col1α1). Furthermore, recombinant mouse periostin directly induced Col1α1 expression in vitro, and this effect was inhibited by PI3K/Akt kinase inhibitor LY294002. Conclusions Periostin plays an essential role in the pathogenesis of scleroderma. Disclosure of Interest None Declared