@InBeforeTheCure, calling your here primarily but if others want to chime in/discuss please do. I'll try to explain it in a simple way, so everyone can understand it. It has to do with SHH and I'm really wondering if it wasn't a black day for us all when development of the small molecule was ceased to due safety concerns;
http://phx.corporate-ir.net/phoenix.zhtml?c=123198&p=irol-newsArticle&ID=997941&highlight=
In Androgenetic Alopecia as a hair follicle miniaturizes based on observation we see that the DP size decreases. Apparently DP size governs hair follicle size as shown in studies. Furthermore Cotsarelis has shown that in bald scalp in men retains hair follicle stem cells but there is a lack of progenitor cells. Now we can perhaps conclude that there is a lack of progenitor cells and DP cells. The DP seems to control progenitors though as shown in some papers
(1)..
How dermal papilla (DP) niche cells regulate hair follicle progenitors to control hair growth remains unclear. Collectively, our data identify Sox2 as a key regulator of hair growth that controls progenitor migration by fine-tuning BMP-mediated mesenchymal-epithelial crosstalk.
Here is another study;
The size and shape of the hair shaft is dependent on the number and activity of hair progenitor cells, which is in turn dependent on the number and activity of the dermal papilla cells that comprise their niche. Our work in the mouse has shown that a reduction in dermal papilla cell number can cause the follicular decline and telogen arrest observed in human hair thinning and loss. However, it has also revealed that dermal papilla number is actively regulated in the context of the regenerative phase of the hair cycle
Therefore based on this we could perhaps say that the earlier event of the chain is happening in the DP rather than the progenitors. After all it would be illogical to think otherwise. As the hair progenitor cells seem to be dependent on the activity of the dermal papilla niche. The observations in a miniaturized hair follicle confirm this. Indeed a decline of DP niche function would probably automatically mean a decline of progenitor cells.
So perhaps it's logical to assume that the decline of DP is one of the first events that happens in the hair follicle as Androgenetic Alopecia rages through. However as you can see from the latest quote the dermal papilla number is actively regulated in the context of the regenerative phase of the hair cycle. Meaning that between cycling through anagen - catagen - telogen the numbers and size of DP is not static. So perhaps the primary event is indeed not a decline of DP but rather a problem with the event that governs this phenomenon. We don't know exactly from where the DP get's actively regulated in a hair follicle cycle... However on the other hand one should know that the DP is the main and primary androgen site of the hair follicle.
But let's just all put this together and look at it from a more simple view. Let's just assume that because of Androgenetic Alopecia some cell function stops somewhere. I mean can't we actually look at it from such a simple view? After all something has to stop functioning the way it supposed to do that leads to the miniaturization process. Look at it from an abstract point of view.
Now I have already linked to many studies that seem to point out senescence/cell cycle arrest in DP, here are a few;
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828374/
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http://www.ncbi.nlm.nih.gov/pubmed/17989730
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http://www.ncbi.nlm.nih.gov/pubmed/18702626
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http://www.ncbi.nlm.nih.gov/pubmed/25647436
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http://www.papersearch.net/view/detail.asp?detail_key=27731029
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http://www.ncbi.nlm.nih.gov/pubmed/25778683
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https://www.researchgate.net/public...ith_a_microRNA_amplification_profiling_method
Hell, so let's just pick last study of the differential expression analysis between balding and non-balding DP and the micro RNA's involved in there and what they say about that;
Of these five microRNAs selected, significant upregulation of four microRNAs (miR-221, miR-125b, miR-106a, miR-410) in balding compared with nonbalding papillae was confirmed by real-time PCR
MiR-221, one of the upregulated microRNAs in this study, has been shown to be deregulated in many types of cancers and diseases. MiR-221 as well as miR-222 is upregulated The functional targets of miR-221, verified in previous studies, are receptor tyrosine kinase, c-kit, and the cyclin-dependent kinase inhibitors p27 ⁄kip1 and p57 ⁄kip2.35
The dual role of miR-125b in controlling cell proliferation and apoptosis has been defined in studies revealing its upregulation in several prostate cancer (CaP) cell lines. Bak1, a proapoptotic Bcl2 family member,39 and HER2 and HER3, two tumour suppressor genes found in breast cancer, are the direct experimentally verified functional targets of miR-125b.
Upregulation of miR-106a has been found in prostate and other cancers.28,48 The verified functional targets of this microRNA are Mylip, Rbp1-like, Hipk3, RB1and CDKN1 ⁄P21 of which the first three lead to T-cell leukaemia tumorigenesis48 and RB1 and CDKN1 ⁄P21 are the targets of miR-106a in different cancers.28,50 However, upregulation of this microRNA in balding dermal papilla cells in this study, and the opposite behaviour seen in these cells in contrast to cancer cells, signify the importance of future studies to discover the mechanisms correlating the functional targets of this microRNA in dermal papilla cells and the complex network of signalling cascades and regulatory factors including androgen receptor signalling.
Now I wanted to divide factors. There would be factors that would stop the cells from functioning and there are factors that would try to do their best to push the cells to start functioning the way they did in the beginning. So if we take some factors from the above studies and divide them
- Factors that stop cells from functioning
CDKN1/P21, BAK1, P27, P57, P51, pRB etc.
- Factors that would oppose some of the above factors (depends on the context though, it's more difficult in reality)
WNT, SHH, MYC, JUN, FOS, MAPK/ERK pathway, BCL-2 etc, Cyclin D1, growth factors...
Now the thing is let's look at observations what treatments actually grow hair. I'm going to pick two that is minoxidil and 17b-estradiol
Minoxidil might have impact on
- P21 decrease
- BCL-2/BAX
- B-catenin (WNT pathway)
-P53 decrease
- ERK/AKT
- Adenosine upregulation,
- VEGF (among other growth factors)
- PGE2
Now you can see that minoxidil not only does it seem to stimulate some factors that would oppose some of the bad guys, it might even have impact on some of these bad guys by decreasing them. I can link to any study showing these factors and implications with minoxidil btw.
Now let's look at some factors 17b-estradiol influences, it's much and complicated anyway;
The molecular mechanisms of estrogen action are relatively well investigated, but only a few target genes with consensus ERE (primary-responsive genes) are known so far, such as progesterone receptor, prolactin, lactoferrin, ovalbumin, vitellogenin, cathepsin D1, pS2, glucose-6-phosphate dehydrogenase, c-fos, c-jun, c-myc and choline acetyltransferase. There are more genes activated eventually by estrogen but without apparent ERE: EGF, EGFR, cyclin D1 and others,
But yeah if you look at this study;
http://press.endocrine.org/doi/full/10.1210/er.2006-0020. You can see more interactions with estrogen with the MAPK pathway, WNT and many more.
Can we say based on this that perhaps why minoxidil and estrogen work is partly through this mechanism? Inhibit androgen/AR. Add minoxidil and estrogen. Then you get rid of the pathway chain in the first place (androgen/AR), but secondly you are now adding 2 molecules that will try their best to push these cells to performing their normal function again?
