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Title : " An analysis of gene expression data involving examination of signaling pathways activation reveals new insights into the mechanism of action of minoxidil topical foam in men with androgenetic alopecia " Full Text uploaded . June 2017
Abstract :
Androgenetic alopecia is the most common form of hair loss. Minoxidil has been approved for the treatment of hair loss, however its mechanism of action is still not fully clarified. In this study, we aimed to elucidate the effects of 5% minoxidil topical foam on gene expression and activation of signaling pathways in vertex and frontal scalp of men with androgenetic alopecia. We identified regional variations in gene expression and perturbed signaling pathways using in silico Pathway Activation Network Decomposition Analysis (iPANDA) before and after treatment with minoxidil. Vertex and frontal scalp of patients showed a generally similar response to minoxidil. Both scalp regions showed upregulation of genes that encode keratin associated proteins and downregulation of ILK, Akt, and MAPK signaling pathways after minoxidil treatment. Our results provide new insights into the mechanism of action of minoxidil topical foam in men with Androgenetic Alopecia.
Discussion :
Our analysis revealed that both genes and non-coding RNAs were differentially expressed between vertex and frontal scalp before and after treatment with MTF 5%.
We observed variations in gene expression in the two scalp regions before treatment. Several genes, including genes induced by oxidative stress and growth factors (DUSP1, CYR61),26–28 and non-coding RNAs were upregulated in frontal compared to vertex scalp, while the expression of pseudogene MSL3P1 that may be involved in chromatin remodeling and regulation of transcription was decreased. These results suggest that gene expression in hair follicles in vertex versus frontal scalp of patients with Androgenetic Alopecia may not be completely identical and exhibit different molecular signatures.
In general, vertex and frontal scalp showed similar molecular response to MTF 5% treatment. The strong upregulation of keratin-associated genes in both the vertex and frontal regions was a distinctive feature of responding patients, while patients who showed minimal response to MTF 5% treatment did not exhibit a similar level of upregulation of keratin-associated genes. The expression of several non-coding RNAs was significantly decreased in both scalp regions after treatment. It should be noted that keratinization-related genes were downregulated in the frontal scalp of both responders and placebo control patients. Thus, it is not clear whether the decreased expression of late cornified envelope protein 3D (LCE3D) was caused by the MTF 5% treatment or other as yet unidentified factors. We also observed regional variations in gene expression after treatment with MTF 5%. Collagen type VI alpha 6 chain (COL6A6), fatty acid and lipid metabolism genes (ACOT4, CIDEA) and several non-coding 8 RNAs were upregulated in frontal scalp compared to vertex. The downregulated genes included keratinencoding and keratin-associated genes as well as genes that play a role in cation channel activity and extracellular matrix binding. It is tempting to speculate that these differences in gene expression reflect the underlying mechanism of the response of hair follicles from two scalp regions to MTF 5% treatment. Baseline regional variations between frontal and vertex scalp were also visible upon pathway level examination. Thus, IL-2, which is being studied in the context of alopecia areata,29 and ILK, a key mediator in integrin signal transduction, were upregulated pathways identified in frontal compared to vertex scalp.
The following pathways were also upregulated in frontal versus vertex scalp before treatment: MAPK (facilitates the survival of dermal papilla cells30), TGF-beta (induces catagen31), JAK/STAT (prevents anagen reentry32), PTEN, Akt (promotes dermal papilla cells survival and anagen initiation33,34). The downregulated pathways included IL-6, which may provoke inflammation, and Presenilin action in Notch and Wnt signaling (NCI) pathways.
It has been shown that activation of Notch signaling is necessary for keratinocyte differentiation, and Wnt signaling drives hair follicle morphogenesis, hair shaft differentiation, hair cycling induction and maintenance.37–42 ILK, Akt, and MAPK pathways became downregulated in both vertex and frontal scalp of responders after treatment with MTF 5%.
Previous studies have shown that Akt and MAPK pathways promote dermal papilla cell survival, so the effect of minoxidil on these pathway requires further clarification. JAK/STAT signaling and Ras pathways were downregulated in vertex scalp of patients who responded to MTF 5% treatment. JAK/STAT inhibition should promote hair growth, while Ras pathway regulates cellular proliferation, differentiation, and senescence by stimulating various parallel effector pathways.43 Protein digestion and absorption pathway, which includes several collagen-encoding genes, was significantly upregulated in the frontal scalp of responders.
MTF 5% treatment also caused upregulation of mTOR pathway in the frontal scalp region. It is known that mTOR pathway promotes hair follicle stem cells proliferation and activation, and is activated at the moment of telogen-to-anagen transition.44,45 9 The results of our analysis suggest that vertex and frontal scalp of
Androgenetic Alopecia patients showed generally similar response to minoxidil treatment implying that minoxidil can be recommended for both vertex and frontal scalp. However, there were some differences in response to the treatment at the level of gene expression and signaling pathways response. Both scalp regions showed upregulation of genes that encode keratin-associated proteins and downregulation of ILK, Akt, and MAPK signaling pathways after MTF 5% treatment, suggesting that control of inflammation in conjunction with keratin stimulation may contribute to the improvement of hair growth disorders. To our knowledge this is the first time that regional variations in the activation of signaling pathways before and after treatment with MTF 5% has received significant attention. These results were based on available data from a study involving a minoxidil foam product,25 and as such may not be representative of all products containing minoxidil.
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