Br J Dermatol. 2012 May;166(5):1035-42. doi: 10.1111/j.1365-2133.2012.10856.x.
[h=1]Hair follicle stem cell differentiation is inhibited through cross-talk between Wnt/β-catenin and androgen signalling in dermal papilla cells from patients with androgenetic alopecia.[/h]
Leirós GJ,
Attorresi AI,
Balañá ME.
[h=3]Source[/h]Fundación Pablo Cassará, Instituto de Ciencia y TecnologÃa Dr César Milstein, Consejo Nacional de Investigaciones CientÃficas y Técnicas, Ciudad de Buenos Aires, Argentina.
[h=3]Abstract[/h][h=4]BACKGROUND:[/h]Hair follicle (HF) regeneration begins when signals from the mesenchyme-derived dermal papilla cells (DPC) reach multipotent epidermal stem cells in the bulge region. Wnt/β-catenin signalling is known to affect mammalian hair growth positively. In androgenetic alopecia (Androgenetic Alopecia), androgens cause HF miniaturization through a mechanism that remains unclear. Circulating androgens act on DPC and alter paracrine factors that influence hair epithelial cells.
[h=4]OBJECTIVES:[/h]To elucidate the role of androgens in dermal papilla-induced differentiation of HF stem cells.
[h=4]METHODS:[/h]HF stem cell differentiation was evaluated in a coculture model with DPC or culturing with media conditioned by DPC after activation of androgen and Wnt/β-catenin signalling pathways. To study the molecular cross-talk between the androgen and Wnt signalling pathway in DPC, we analysed the expression and activation of downstream Wnt signalling molecules in the presence of androgens.
[h=4]RESULTS:[/h]In a coculture model with human DPC from patients with Androgenetic Alopecia and HF stem cells, we observed that androgens abrogate hair differentiation evaluated by hair-specific keratin 6 expression. Wnt signalling activation restored the ability of androgen-treated DPC to induce differentiation. Androgen treatment revealed a significant decrease in the cytoplasmic/total β-catenin protein ratio and upregulation of the activity of glycogen synthase kinase-3β in DPC, indicative of canonical Wnt pathway inhibition.
[h=4]CONCLUSIONS:[/h]These results suggest that androgens deregulate DPC-secreted factors involved in normal HF stem cell differentiation via the inhibition of the canonical Wnt signalling pathway.
© 2012 The Authors. BJD © 2012 British Association of Dermatologists.
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Endocrinology. 2010 May;151(5):2373-80. doi: 10.1210/en.2009-1474. Epub 2010 Mar 16.
[h=1]A mouse model of androgenetic alopecia.[/h]
Crabtree JS,
Kilbourne EJ,
Peano BJ,
Chippari S,
Kenney T,
McNally C,
Wang W,
Harris HA,
Winneker RC,
Nagpal S,
Thompson CC.
[h=3]Source[/h]Department of Tissue Repair, Wyeth Research, Collegeville, Pennsylvania 19426, USA.
[h=3]Abstract[/h]Androgenetic alopecia (Androgenetic Alopecia), commonly known as male pattern baldness, is a form of hair loss that occurs in both males and females. Although the exact cause of Androgenetic Alopecia is not known, it is associated with genetic predisposition through traits related to androgen synthesis/metabolism and androgen signaling mediated by the androgen receptor (AR). Current therapies for Androgenetic Alopecia show limited efficacy and are often associated with undesirable side effects. A major hurdle to developing new therapies for Androgenetic Alopecia is the lack of small animal models to support drug discovery research. Here, we report the first rodent model of Androgenetic Alopecia. Previous work demonstrating that the interaction between androgen-bound AR and beta-catenin can inhibit Wnt signaling led us to test the hypothesis that expression of AR in hair follicle cells could interfere with hair growth in an androgen-dependent manner. Transgenic mice overexpressing human AR in the skin under control of the keratin 5 promoter were generated. Keratin 5-human AR transgenic mice exposed to high levels of 5alpha-dihydrotestosterone showed delayed hair regeneration, mimicking the Androgenetic Alopecia scalp. This effect is AR mediated, because treatment with the AR antagonist hydroxyflutamide inhibited the effect of dihydrotestosterone on hair growth. These results support the hypothesis that androgen-mediated hair loss is AR dependent and suggest that AR and beta-catenin mediate this effect. These mice can now be used to test new therapeutic agents for the treatment of Androgenetic Alopecia, accelerating the drug discovery process.
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[h=1]Keratinocyte Growth Inhibition through the Modification of Wnt Signaling by Androgen in Balding Dermal Papilla Cells[/h]
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682470/
ontext/Objective: Androgen induces androgenetic alopecia (Androgenetic Alopecia), which has a regressive effect on hair growth from the frontal region of the scalp. Conversely, Wnt proteins are known to positively affect mammalian hair growth. We hypothesized that androgen reduces hair growth via an interaction with the Wnt signaling system. The objective of this study was to investigate the effect of androgen on Wnt signaling in dermal papilla (DP) cells.
Design: The effect of androgen and Wnt3a on keratinocyte proliferation was measured by use of a coculture system consisting of DP cells and keratinocytes. The molecular mechanisms of androgen and Wnt pathway interactions in DP cells were examined by analyzing the expression, intracellular localization, and activity of the androgen receptor (AR) and also downstream Wnt signaling molecules.
Results: Wnt3a-dependent keratinocyte growth was suppressed by the addition of dihydrotestosterone in coculture with DP cells that were derived from Androgenetic Alopecia patients, but growth was not suppressed in coculture with DP cells from non-Androgenetic Alopecia males. Whereas DP cells from both scalp regions expressed AR protein, the expression levels of AR and cotranslocation with β-catenin, a downstream Wnt signaling molecule, were higher in DP cells of Androgenetic Alopecia patients than in DP cells from non-Androgenetic Alopecia males. In addition, significant suppression of Wnt signal-mediated transcription in response to dihydrotestosterone treatment was observed only in DP cells from Androgenetic Alopecia patients.
Conclusion: These results suggest that Wnt signaling in DP cells is regulated by androgen and this regulation plays a pivotal role in androgen’s action on hair growth.