Big New Genome Wide Association Study On Androgenetic Alopecia - Preprint

[Swoop]

That's a complicated question which has barely been explored, so it will probably be many years before we have a satisfactory answer to it. I think an even more interesting question is why susceptibility to androgen-induced hair loss "switches on" in particular HFs at a particular age. Hamilton showed that while 20-year-old castrates injected with testosterone lose hair at the same rate as normal 20-year-olds, but castrates injected with testosterone in their 60s can lose all of their hair within months. It seems then that in these 60-year-old castrates, there is some latent androgen sensitivity which exists independent of exposure to androgens, but it needs that DHT trigger to set it off.

Very interesting indeed. That's a brutal and painful observation too imo. What's your take on that?

Also look at the following presentation; http://www.sinclairdermatology.com....rogenic-Alopecia-new-insights-August-2014.pdf

Kinda interesting also that the "secondary hair follicles" miniaturize first apparently in Androgenetic Alopecia diffuse hair loss and the primary as last (APM loses connection with primary as last).

How would you explain that?

 

[Armando Jose]

Thank you Swoop for the link,
IMO,, APM is involucrated in the release of sebum from SG. Could be a link?

 

[Grasshüpfer]

I think an even more interesting question is why susceptibility to androgen-induced hair loss "switches on" in particular HFs at a particular age.

How about this:

Hypoxia enhances ligand-occupied androgen receptor activity.
https://www.ncbi.nlm.nih.gov/pubmed/22266320

Hypoxia, notch signalling, and prostate cancer
http://www.nature.com/nrurol/journal/v10/n7/full/nrurol.2013.110.html

I don't want to channel squeegee, but it seems to be a simple explanation for the switch. Occhams razor and stuff. With progressing time the androgen receptor is upregulated in a linear manner. Therefore androgens hit the follicles harder in aged men.

Transplanted follicles then have a head start of maybe 20 years, before their Ar is sensitive enought to cause damage to the hf. Plus androgen levels are generally lower in aged men.

 

[mr_robot]

Kinda interesting also that the "secondary hair follicles" miniaturize first apparently in Androgenetic Alopecia diffuse hair loss and the primary as last (APM loses connection with primary as last).

How would you explain that?

Slightly OT, I've been wondering about this about my hairloss for a while, I have very few follicular units that have more than one hair follicle. I'm wondering if the primary is still strong does that make the chances of recovering the secondary ones greater.

 

[mr_robot]

That's a complicated question which has barely been explored, so it will probably be many years before we have a satisfactory answer to it. I think an even more interesting question is why susceptibility to androgen-induced hair loss "switches on" in particular HFs at a particular age. Hamilton showed that while 20-year-old castrates injected with testosterone lose hair at the same rate as normal 20-year-olds, but castrates injected with testosterone in their 60s can lose all of their hair within months. It seems then that in these 60-year-old castrates, there is some latent androgen sensitivity which exists independent of exposure to androgens, but it needs that DHT trigger to set it off.

Would n't that suggest that anrogen sensitivity is aging related? Which would make sense as some people age better then others.

 

[Dench57]

sebum

 

[kiwipilu]

hahaha dafoe going psycho. Same facial expression as me when I see a treament ends up being a scam.. btw what movie is this?

 

[Armando Jose]

Touched

 

[InBeforeTheCure]

Very interesting indeed. That's a brutal and painful observation too imo. What's your take on that?

Another study along these lines by Obana et al. in stumptailed macaques:

Hair-follicle regression in the bald scalps of stumptailed macaques develops after puberty, which corresponds to an elevation of serum testosterone and dihydrotestosterone. Using the cultured cells from the pre- and postpubertal macaques, we examined the role of dermal papilla cells in testosterone-induced inhibition of outer root sheath cell proliferation. Testosterone showed no effects on proliferation of either dermal papilla cells or outer root sheath cells cultured alone. Testosterone-induced inhibition of outer root sheath cell proliferation occurred only in coculture with dermal papilla cells derived from the bald scalps of adult macaques but not with dermal papilla cells from the hairy occipital scalps of adult macaques or the prebald frontal scalps of juvenile macaques. Furthermore, RU 58841, an androgen receptor blocker, antagonized this testosterone-elicited inhibition. Together our data indicate that the inhibitory effect of testosterone on proliferation of epithelial cells is age dependent, and androgen may play an essential role in hair growth either by inducing repressor(s) from dermal papilla cells, which may then inhibit the growth of epithelial cells of the hair follicle, or by inducing growth factor(s) from dermal papilla cells, which, in turn, may trigger the induction of some repressors in epithelial cells, thereby inhibiting the epithelial cell growth. Our animal studies also showed that RU 58841 has a dramatic effect on hair regrowth in the bald frontal scalp of the stumptailed macaque, which may further support our in vitro culture studies showing that antiandrogens can antagonize testosterone-elicited hair growth. In summary, our studies may provide a model for further isolation of androgen-regulated repressor(s)/growth factors, which may help control hair growth and baldness.

What those age-dependent changes are I have no idea. Too bad they didn't try DHT as well to see if local 5-alpha-reductase activity might account for some of this, as well as testing AR expression between the juvenile and adult DPCs.

Also look at the following presentation; http://www.sinclairdermatology.com....rogenic-Alopecia-new-insights-August-2014.pdf

Kinda interesting also that the "secondary hair follicles" miniaturize first apparently in Androgenetic Alopecia diffuse hair loss and the primary as last (APM loses connection with primary as last).

How would you explain that?

Are there any studies showing that the APM is really that critical for HF function though, besides direction/piloerection? In any case, Fujiwara et al. determined the mechanism by which the APM attaches to the HF. They found that Wnt signaling in bulge HFSCs upregulates nephronectin, which is deposited onto the basement membrane. Nephronectin binds to α8β1-integrin in APM progenitors, and this is what attaches the APM to the bulge. Also, HFs formed by Tsuji's bioengineered hair follicle germs form attachments to the APM. It could be then that in A.G.A., there's some defect somewhere along the line in this process, in which case the detachment of the APM could be a secondary effect of a more serious problem upstream such as stem cell dysfunction or defects in Wnt signaling. If this is the case, detachment of the APM first in secondary follicles would be the result of such a defect occurring in those follicles first, with eventually the primary follicle suffering the same fate. But why the secondary follicles go first I don't know.

How about this:

Hypoxia enhances ligand-occupied androgen receptor activity.
https://www.ncbi.nlm.nih.gov/pubmed/22266320

Hypoxia, notch signalling, and prostate cancer
http://www.nature.com/nrurol/journal/v10/n7/full/nrurol.2013.110.html

I don't want to channel squeegee, but it seems to be a simple explanation for the switch. Occhams razor and stuff. With progressing time the androgen receptor is upregulated in a linear manner. Therefore androgens hit the follicles harder in aged men.

Transplanted follicles then have a head start of maybe 20 years, before their Ar is sensitive enought to cause damage to the hf. Plus androgen levels are generally lower in aged men.

In the first paper, they don't find the exact mechanism through which HIF-1 stabilization increases AR transcriptional activity. However, they do state that it's not due to AR upregulation.

These effects were not due to increased expression of the AR or HIF-1α as a result of hypoxia and DHT treatment.

Of course, it could be that the mechanism could occur in prostate cells but not in DPCs. Transcription factor binding sites, for example, are quite cell-type specific. I also don't understand the point about transplanted hairs??? If due to tissue hypoxia, HIF-1 would be stabilized within minutes.

Would n't that suggest that anrogen sensitivity is aging related? Which would make sense as some people age better then others.

Yeah, there's clearly some interaction between genetics, androgens, and aging.

 

[InBeforeTheCure]

A study on Pax1 in skeletal development published last month: A developmental transcriptomic analysis of Pax1 and Pax9 in embryonic intervertebral disc development

The Pax1 locus is the #2 most associated in many GWAS done on A.G.A including this one, behind only the androgen receptor gene. The authors mention that Pax1 regulates a number of genes involved in the BMP, TGF-beta, and Wnt pathways, which seem to be implicated in A.G.A as well. But maybe the most interesting thing they say is this:

Also, VB enriched genes identified by Sohn et al (2010) were repressed by both Pax1/Pax9 and TGF-B (Ebf1, Gdf10, Alcam, Nr2f2).

Marcinska et al., who did a small-scale GWAS on A.G.A, found an epistatic interaction between the Pax1 and Ebf1 loci.

...taking into account the interaction between rs929626 [in EBF1] and rs1998076 [near PAX1] (P<0.001). According to the entropy-based analysis, this interaction has redundant character, (i.e. redundant information from both factors).

Both are dermal papilla signature genes (see hair-gel.net).

 

[Gone]

Well, most people were looking for something in the body to f*** with that wasn't AR, so it looks like we have something. Great job bringing this to light. I wonder if Pax1 is upregulated or down regulated in Androgenetic Alopecia, and what the outcome of tampering with it will be.

 

[Tracksterderm]

Yeah, there's clearly some interaction between genetics, androgens, and aging.

Well, soon enough aging will be taken out of the equation. Lets just hope we won't stay young and bald.

https://www.eurekalert.org/pub_releases/2016-12/si-tbt120916.php

 

[abcdefg]

Very interesting indeed. That's a brutal and painful observation too imo. What's your take on that?

Also look at the following presentation; http://www.sinclairdermatology.com....rogenic-Alopecia-new-insights-August-2014.pdf

Kinda interesting also that the "secondary hair follicles" miniaturize first apparently in Androgenetic Alopecia diffuse hair loss and the primary as last (APM loses connection with primary as last).

How would you explain that?

I think sensivity to androgens continually increases as you get older which is why propecia or whatever AA loses effectiveness with time as you get older. Propecia keeps working, but hair keeps getting more sensitive. You still need that DHT trigger though like it says. Some men at very old ages never go bald, but they were never susceptible to male pattern baldness to begin with like elvis or ronald reagan. So it cant be just aging or every man would be affected by it.
The answer is just buried deeper in genetics or the molecular pathways in male pattern baldness which we will probably be dead before its all ironed out

 

[InBeforeTheCure]

Well, most people were looking for something in the body to f*** with that wasn't AR, so it looks like we have something. Great job bringing this to light. I wonder if Pax1 is upregulated or down regulated in Androgenetic Alopecia, and what the outcome of tampering with it will be.

AFAIK, there's nothing out there that directly targets Pax1 unfortunately.

Well, soon enough aging will be taken out of the equation. Lets just hope we won't stay young and bald.

https://www.eurekalert.org/pub_releases/2016-12/si-tbt120916.php

Well, a 30 percent increase in lifespan is fantastic, but "taken out of the equation" would be a slight exaggeration.

The answer is just buried deeper in genetics or the molecular pathways in male pattern baldness which we will probably be dead before its all ironed out

With how slowly things progress in the hair loss field, it wouldn't surprise me.

 

[Tracksterderm]

Well, a 30 percent increase in lifespan is fantastic, but "taken out of the equation" would be a slight exaggeration.

"Our study shows that aging may not have to proceed in one single direction," says Juan Carlos Izpisua Belmonte, a professor in Salk's Gene Expression Laboratory and senior author of the paper appearing in the December 15, 2016 issue of Cell. "It has plasticity and, with careful modulation, aging might be reversed."

 

[InBeforeTheCure]

^^^ Yes, but aging still happens -- it's not completely out of the equation just yet.

Still fascinating. This could be effective against senescent alopecia, since loss of Krt15+ stem cells to DNA damage seems to play a role in that. This cyclical 4-factors treatment mostly prevents this from happening:

"Moreover, analysis of adult stem cells populations revealed a partial restoration of the number of satellite cells (i.e., Pax7-positive cells) in skeletal muscle and hair follicle stem cells (Cytokeratin-15-positive cells) in LAKI 4F mice subjected to cyclic induction of OSKM compared to untreated animals (Figures 5F and 5G)."

 

[Swoop]

Bump for greatness. You still around @InBeforeTheCure? Miss your posts .

Also as others have already linked this study: http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1006594.

 

[Swiss_Tampons]

I wish @InBeforeTheCure was as active as the shitposters that flood the forum every day. Or at least as active as 0.1% of the average posting rate of the ''impact session''. But hey @Swoop, you're missing too! I tagged you in your own thread and you didn't answer

 

[InBeforeTheCure]

Bump for greatness. You still around @InBeforeTheCure? Miss your posts .

Also as others have already linked this study: http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1006594.

Cool. They also included an analysis with something called DEPICT which wasn't in the preprint (Supplementary Table S5). This tests for pathway enrichment in genes near GWAS hits. Some interesting categories: GLI3 subnetwork and KEGG_MTOR_SIGNALING_PATHWAY, both in the top 10. RUNX2 subnetwork, KEGG_PROSTATE_CANCER, TWIST1 subnetwork, SMAD2 subnetwork, REACTOME_PIP3_ACTIVATES_AKT_SIGNALING, REACTOME_PI3KAKT_ACTIVATION, SMAD3 subnetwork, and SMAD1 subnetwork. Also various categories involved in transcriptional regulation, and in the paper they also mention multiple genes involved in the Wnt pathway.

The million dollar question though is: How do all these components interact with each other and with androgens to cause balding? Maybe we can look for some hints in Chew et al.'s microarray study. Here's an example...

Twist1 (and also Twist2 obviously) is a basic helix-loop-helix (bHLH) transcription factor. To bind DNA, bHLH transcription factors typically (maybe always?) need to dimerize with other bHLH proteins. So Twist1 can dimerize with another Twist1 protein (Twist1 homodimer) or it can dimerize with E-proteins (which are also bHLH) such as Tcf3 or Tcf12 (Twist1 heterodimer), and also it can dimerize with things like Hand1 and Hand2. Regulation of gene expression by Twist differs depending on its dimer composition; for example, Twist1 heterodimers downregulate FGFR2 in cranial sutures while Twist1 homodimers upregulate FGFR2. Twist1 and Tcf12 are both GWAS hits for A.G.A, so Twist1 dimer composition is probably important for us. Twist1 is also the most common mutation in Saethre-Chotzen syndrome (SCS), characterized by premature closing of the cranial sutures (Twist1 heterodimers keep these sutures open), and Tcf12 mutations are also known to cause SCS.

Now, one way that cells can control Twist1 dimer composition is through regulation of Inhibitor of DNA Binding expression (ID1, ID2, ID3, and ID4), which are helix-loop-helix (HLH) proteins that lack the basic domain and can't bind DNA. ID proteins compete with bHLH TFs for E-proteins, so when ID expression is low comparatively more Twist heterodimers will be formed, and when ID expression more Twist homodimers will be formed.

OK, that's hopefully enough background. So look what happens to ID1, ID2, and ID3 expression in dermal papilla cells with exposure to DHT. The top left graph is in balding DPCs treated with 10nM DHT, the top right is balding DPCs treated with 1nM DHT, the bottom left is in non-balding DPCs treated with 10nM DHT, and the bottom right is in non-balding DPCs treated with 1nM DHT. Notice how in all four cases, ID1 and ID2 spike rapidly after treatment with DHT within 15 minutes. ID3 also spikes rapidly in the non-balding cells, but in the balding cells it lags a bit for some reason. Then, after a few hours, ID expression returns to normal.

The spike in ID expression happens within 15 minutes, which is probably too fast to be the result of classical genomic regulation by AR. Instead, this would be a response to non-genomic AR signaling. IDs are canonical target genes of SMADs, and indeed, if you take the list of genes upregulated at the 30 minute mark and analyze them with TFacts, you'll find that they're mostly enriched for SMAD target genes. Therefore, the most likely explanation for the spike in ID expression is the known upregulation of TGF-beta1 by DHT. The timing is also right -- that one Philpott study found the induction of TGF-beta1 by DHT to be less than an hour, so they concluded that this was probably the result of non-genomic AR signaling. The drop in ID expression after a few hours, when AR would be predominantly nuclear, is also consistent with this interpretation. The one problem is that Chew's microarray didn't detect TGFB1 expression at all, so maybe their probeset didn't detect it for some reason?

But anyway, here you have a possible connection between some of the GWAS hits -- SRD5A2, AR, TGFB1, TWIST1, TWIST2, and TCF12. Runx2 and Runx3, which bind SMADs, are also major downstream modulators of TGF-beta. So probably both expression levels of the upstream components of this pathway as well as their downstream modulators can give different "outputs" when DPCs are exposed to androgens. Also, given that Twist1 knockout mice stay in anagen forever(?), Twist1 must play a very important but unexplored role in hair follicle biology.

What do you think?

I wish @InBeforeTheCure was as active as the shitposters that flood the forum every day. Or at least as active as 0.1% of the average posting rate of the ''impact session''

Thanks. But come on, the impact section is glorious.

 

[Armando Jose]

The million dollar question though is

why only affect to certains hairs in scalp??