What’s new in hair — October 2015 | Dr. Claire A. Higgins
J Am Acad Dermatol. 2015 Oct 27. pii: S0190-9622(15)02134-9. doi:10.1016/j.jaad.2015.08.063.
Autoimmune diseases are complex genetic traits, thought to be caused by the combination of a multitude of different factors. They can impact a number of tissues, although a tissue commonly affected by autoimmune disorders is the skin. In this paper, Gill et al conduct a manual chart review of 1873 patients diagnosed with vitiligo over a 10 year period. They found that 19.8% of patients assessed presented with at least one other autoimmune disorder in addition to vitiligo. The most common of these was Thyroid disease, observed in 12.3% of patients with vitiligo, while alopecia areata was the second most common comorbid disease, impacting 3.8% of patients. There is therefore a significantly higher prevalence of alopecia areata in patients with vitiligo compared to the general population.
Science Advances Vol. 1, no. 9, e1500973. doi: 10.1126/sciadv.1500973
In alopecia areata, there is a cytotoxic T cell (CTL) feed forward loop that is exacerbated with disease, with CTLs releasing IFNγ resulting in follicle inflammation, which in turn promotes proliferation and an increase in CTLs. Last year, the Christiano group demonstrated that the Jak inhibitors Ruxolitinib and Tofacitinib could break this feed forward loop, and promote hair growth in individuals in alopecia areata. However, inhibition of CTLs in the follicle macroenvironment cannot be all that is required for hair regrowth, else other treatments would have worked previously. In this follow up paper, Harel et al demonstrate that the Jak inhibitors Ruxolitinib and Tofacitinib also have a localised effect on the follicle. In murine studies, they show that Jak inhibitors promote proliferation of stem cell progenitors in quiescent telogen follicles. They go on to show that these Jak inhibitors can also promote faster hair growth in human anagen hair follicles, using an organ culture model. This dual effect of Jak inhibitors, both in and outside the follicle, suggests that they may be useful therapeutics for other hair loss conditions in addition to autoimmune related disorders.
J Invest Dermatol. 2015 Oct 13. doi: 10.1038/jid.2015.402.
In 2010, the first Genome-Wide Association Study (GWAS) into alopecia areata identified 8 loci that were significantly associated with disease. Subsequently, a Meta-analysis published this year increased the number of significantly identified loci to 14. In this paper, Petukhova et al rationalise that understanding the biological implication of GWAS data requires pathway analysis and gene network construction. They performed pathway analysis on genes located within 1KB of significant SNPs on the 14 identified loci, identifying 27 overrepresented pathways which were all associated with immune system processes or immune-related diseases. These included ‘Antigen processing and presentation’, the ‘Co-stimulatory pathway’, ‘JAK-STAT signalling’ and ‘Autoimmune thyroid disease’. They go on to show that exclusion of the HLA locus in their analysis does not impact the significance of the other results, suggesting these are bona-fide pathways, and potential therapeutic targets for treatment of alopecia areata.
Topical adenosine increases the proportion of thick hair in Caucasian men with androgenetic alopecia.
J Dermatol. 2015 Oct 28. doi: 10.1111/1346-8138.13159.
In vitro, both dermal papilla cells and organ cultured hair follicles respond to adenosine. Not only can adenosine result in transcriptional activation of β-catenin in cultured dermal papilla cells, but adenosine activation can also stimulate phosphorylation of ERK and AKT, and induce expression of several growth factors including FGF7. In this study, Iwabuchi et al assessed the effect of topical adenosine on hair characteristics in Caucasian men with androgenetic alopecia. Adenosine lotion (0.75%) or a placebo were topically applied for 6 months. After 6 months there were no significant differences in baldness grade between the adenosine group and the placebo group. However, the proportion of thick hairs on the scalp compared to the start of the study was significantly increased in the adenosine group, but not in the placebo group. It is well known that the size of the dermal papilla relates directly to the thickness of the hair fibre, and so it is interesting to speculate whether adenosine is altering dermal papilla size, rather than having an effect on the hair cycle.
Mamm Genome. 2015 Oct 19. doi:10.1007/s00335-015-9608-5
Male dominant long hair (MALC) hamsters have a hair coat that is significantly longer than their wildtype counterparts, transmitted via an autosomal recessive mode of inheritance. Although female MALC hamsters do have longer hair than female wild types, male MALC have a significantly longer coat than female MALC hamsters. In this paper, Yoshizawa et al show that hair length in male MALC hamsters shortens with castration, but can be rescued by the addition of testosterone. They also demonstrate that blocking of the Androgen Receptor (AR) can abrogate the effect of testosterone on hair length in castrated MALC males. More interesting is that they go on to demonstrate that a 1bp deletion (c.546delG) in Fgf5 is only present in hamsters with the long haired phenotype, and not wild types. They speculate that this FGF5 mutation impacts AR activation by testosterone, explaining the differences between male and female hamsters with the same mutation. Previously identified mutations in FGF5/Fgf5 appear to have affected both sexes equally, and this is the first paper linking FGF5 with AR activation.
In silico prediction of prostaglandin D2 synthase inhibitors from herbal constituents for the treatment of hair loss.
J Ethnopharmacol. 2015 Oct 6. pii: S0378-8741(15)30167-7. doi: 10.1016/j.jep.2015.10.005.
In 2012, Garza et al demonstrated that balding scalp has elevated levels of Prostaglandin D2 (PGD2). Thus, the search was on for Prostaglandin D2 Synthase (PTGDS) inhibitors that would result in a decrease of PGD2, and could potentially inhibit balding. In this study, Fong et al use in silico approaches to analyse 389 constituents found in 12 traditional Chinese medicines used to treat hair loss, to determine if any are natural PTGDS inhibitors. They assess the ‘docking’ capacity of each constituent to the PTGDS crystal structure, and select 30 with the best binding affinity. These 30 constituents were found to be present within the 6 of the 12 traditional medicines used to treat hair loss. Interestingly, when they evaluated other properties of these constituents, they found them to be highly polar, indicating they would have low skin permeability, thus in their current state these constituents would not be able to penetrate the skin and target the follicle. The next logical step is to perform wetlab studies to validate this in silico data.