Mamiko Tosa

Identification and characterization of Wnt signaling pathway in keloid pathogenesis.

Keloid is characterized by fibroblastic cell proliferation and abundant collagen synthesis. Numerous studies have shown that the Wingless type (Wnt) signaling pathways play key roles in various cellular functions including proliferation, differentiation, survival, apoptosis and migration. The aim of this study was to clarify the role of Wnt signaling pathway in keloid pathogenesis. Primary fibroblast cultures and tissue samples from keloid and normal appearing dermis were used. The expression of Wnt family members, frizzled (FZD)4 receptor, receptor tyrosine kinase-like orphan receptor (ROR)2 and the Wnt signaling downstream targets, glycogen synthase kinase (GSK)3-β and β-catenin were assessed using semi-quantitative RT-PCR, Western blot, or immunohistochemical methods. Of the Wnt family members, Wnt5a mRNA and protein levels were elevated in keloid fibroblasts (KF) as compared to normal fibroblasts (NF). A higher expression of β-catenin protein was also found in KF. No detectable levels of FZD4 receptor and ROR2 proteins were observed in both NF and KF. Functional analysis showed that treatment of NF and KF with recombinant Wnt5a peptide resulted in an increase in protein levels of total β-catenin and phosphorylated β-catenin at Ser33/37/Thr 41 but no significant change in phosphorylated β-catenin at Ser45/Thr 41 positions. In addition, the expression of total GSK3-β protein was not affected but its phosphorylated/inactivated form was increased in NF and KF. Our findings highlight a potential role for a Wnt/β-catenin canonical signaling pathway triggered by Wnt5a in keloid pathogenesis thereby providing a new molecular target for therapeutic modulations.

Clinical Improvement in Psoriasis With Treatment of Associated Hyperlipidemia

Psoriasis is associated with an increased risk of cardiovascular disease, a principal cause of which is atherosclerosis caused by hyperlipidemia. However, it is not known whether treatment of hyperlipidemia in patients with psoriasis lead to clinical improvement in psoriasis condition. In this study, the authors summarize the existing literature relevant to this inquiry. They also describe the potential pathways believed to link psoriasis with atherosclerosis and the role of hyperlipidemia therapy in this setting. A few studies indicated clinical improvement in psoriasis with treatment of associated hyperlipidemia. Some studies showed that a low-fat diet improved psoriasis. Others indicated a decreased risk of psoriasis associated with intake of cholesterol-lowering drugs such as “statins.” Treatment with statins increased lactate dehydrogenase level and diminished Psoriasis Area and Severity Index score, ie, reduced cutaneous lesion in psoriasis. Beneficial effects of statin therapy on psoriasis included downregulation of lymphocyte function-associated antigen-1, inhibition of leukocyte endothelial adhesion, extravasation and natural killer cell activity, inhibition of proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin 1 and 6, lowering of C-reactive protein, promotion of a TH1 to TH2 cells and inhibition of TH1 cytokine receptors on T cells, leading to inhibition of activation of lymphocytes and infiltration into the inflammation sites. Taken together, current literature indicates clinical improvement in psoriasis condition with treatment of associated hyperlipidemia, particularly with statins of which the mechanisms could be attributed to immunomodulatory and anti-inflammatory effects.

Chronologic Change of the Maximum Dimension of Bacillus Calmette-Guerin–Induced Keloids

BACKGROUND Because keloids grow gradually, there is a long time lag until the patients visit the hospital. OBJECTIVE To investigate the chronologic change of the maximum dimension of Bacillus Calmette‐Guerin (BCG)‐induced keloids to provide information on their nature and facilitate early treatment intervention. METHODS Clinical records of patients with keloid treated between 1998 and 2005 were reviewed, and patients with BCG‐induced keloids were assessed with reference to age at onset of keloid, age at first hospital visit, length of the major axis of keloid at first visit, growth rate, and histopathologic features. RESULTS Of 716 patients with keloid, 60 (8.4%) had BCG‐induced keloid. A significant difference was found between mean age at onset and at first visit. The mean length of maximum dimension was 42.4 mm and increased proportionally to age at first visit. Keloids grew rapidly between the ages of 20 and 40, during which time many patients did not seek therapy. Histopathologically, no significant differences were noted between BCG‐induced keloid and non‐BCG keloid. CONCLUSION Early therapeutic intervention might prevent keloids from growing larger, emphasizing a need to provide adequate information on keloid behavior to patients and physicians involved in BCG vaccination. The authors have indicated no significant interest with commercial supporters.

IL-6 Polymorphism and Susceptibility to Keloid Formation in a Japanese Population

and Medical Specialties, University of Genoa and IRCCS AOU San Martino-IST Genoa, Italy; Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK; Department of Biopathology and INSERM U1186, Gustave Roussy, Villejuif, France; Dermatology Unit, Maurizio Bufalini Hospital, Cesena, Italy; Division of Genetic Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA; Melanoma Unit, Dermatology Department, Hospital Clinic, IDIBAPS, Barcelona, Spain and CIBER de Enfermedades Raras, Barcelona, Spain; Sydney School of Public Health, University of Sydney, Sydney, NSW, Australia; INSERM, UMR-946, Genetic Variation and Human Disease Unit, Université Paris Diderot, Paris, France; Departments of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA; The Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, TelHashomer, Israel; Department of Clinical Genetics, University Hospital of Copenhagen, Copenhagen, Denmark; Human Genetics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA; Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre RS, Brazil; Department of OncologyPathology, Karolinska Institutet, Stockholm, Sweden; QIMR Berghofer Medical Research Institute, Herston, QLD, Australia; Institute of Oncology Ljubljana, Zaloska, Ljubljana, Slovenia; Centre for Cancer Research, Westmead Institute for Medical Research and Melanoma Institute Australia, University of Sydney, NSW, Australia; Department of Surgery, Lund University Hospital, Lund, Sweden; Department of Pathology, Escola Paulista de Medicina, UNIFESP, São Paulo, Brazil; Unidad de Lesiones Pigmentadas, Cátedra de Dermatologı́a, Hospital de Clı́nicas, Universidad de la República, Montevideo, Uruguay; Oregon Health Sciences University School of Medicine, Department of Dermatology, Portland, Oregon, USA;

Refractory Leg Ulcers Associated with Klinefelter Syndrome

We present a man with refractory leg ulcers, bilateral varicosis of the lower extremities, and Buerger disease. Autoimmune work-up was negative. However, chromosome analysis showed Klinefelter syndrome (48 XXY). Ulcerative lesions of the lower extremities are a complication of Klinefelter syndrome. To date, the pathogenesis of ulcers in Klinefelter syndrome has not been clarified, but several factors, such as abnormalities of fibrinolysis and prothrombotic states, might be involved. Our present case emphasizes the importance of considering Klinefelter syndrome in the differential diagnosis of a male patient with nonhealing ulcers of the lower extremities.

Examination of Epithelial Mesenchymal Transition in Keloid Tissues and Possibility of Keloid Therapy Target

Background: Keloid is a fibroproliferative skin disorder that is characterized by collagen accumulation and blood vessel proliferation in the reticular layer of the dermis. It is caused by prolonged inflammation after cutaneous injury. Several studies suggested recently that epithelial mesenchymal transition (EMT) is involved in the development of fibrosis. This study assessed whether EMT also participates in keloid development and/or aggravation. Methods: Resected keloid (n = 19) and normal skin (n = 13) samples were subjected to immunohistochemical, immunofluorescent, and Western blot analyses of their expression of epidermal (E-cadherin) and mesenchymal (vimentin) proteins. Results: Immunohistochemical analysis showed that the keloid tissues had more vimentin-positive cells in the epidermis than the normal tissues. When normal primary keratinocytes were cultured with proinflammatory cytokines, the cobblestone-shaped cells changed to a spindle shape and many vimentin-positive cells were detected. When immortalized HaCaT keratinocytes were cocultured in split-well plates with normal or keloid-derived fibroblasts, they also underwent EMT, as indicated by their greater vimentin expression on Western blot analysis compared with HaCaT cells that were cultured alone. Conclusions: EMT was observed in keloid specimens. EMT was induced by inflammatory cytokines and fibroblasts. EMT may be involved in keloid generation and/or aggravation and may have potential as a keloid treatment target.