A possible way to cure baldness... Sonic hedgehog REVIEW

[Giiizmo]

So that all sounds fine and dandy. But where does DHT come into all this? If quiescent cell division is the cause of follicle development, and aging (as this paper claims...) causes this cell division to cease in men with male pattern baldness, then why does inhibiting DHT production or blocking DHT follicle receptor sites result in renewal of the air follicle?

I'd guess they're two processes that can occur concurrently in males - on one hand, male pattern baldness, on the other, loss of hair from senescent stem cells. After all, even men who don't have male pattern baldness experience loss of hair density over their whole scalp as they age.

 

[GoldenMane]

Natural age related thinning is quite a different process to male pattern baldness (though I'm not sure that author is aware of this). Age related thinning results in mild diffuse thinning throughout the scalp, never results in true baldness and does not follow the male horseshoe pattern. It sounds like the process described by this author may be more applicable to age related thinning than male pattern baldness, but she discusses the subject very unambiguously as a potential treatment for male pattern baldness.

If anything she seems confused, doesn't seem to understand the difference in cause between age related thinning and male pattern baldness, and seems to be suggesting that a treatment for age related thinning due to cessation of stem cell division would be applicable to androgenic allopecia. Maybe I'm missing something, but sounds like another half baked hack scientist to me. Don't assume scientists know better. A lot of very mediocre people end up with careers as researchers, you don't have to be the best and brightest to be a researcher...

 

[bushbush]

It seems very odd to have a paper on hairloss completely ignore the role of DHT given that all current treatments are currently focused on DHT inhibition...

DHT is known to play a role, but other processes can also act either up or downstream, for example PDG2. DHT is barely mentioned in the PDG2 literature, yet this does not imply they work in isolation.

Maybe I'm missing something

Yes, you are. The article in question is not a peer-reviewed "paper". It is essentially a blog post that attempts to summarise some of the actual primary literature, such as: http://www.ncbi.nlm.nih.gov/pubmed/24813615

The great thing about science is, if you have the knowledge (which you admit that you don't) you could publish evidence on the contrary...

 

[Mikazz]

Well this is all kind of related.

DHT induces oxidative stress in the hair follicles -> cells are going senescent and stop to divides / inflammation -> hair loss

Stopping DHT will be always better than stopping inflammation.

Oxidative stress is not a linear phenomenon, this is part of the reasons some men has a more diffuse pattern, this is also why most women has a diffuse hair loss. (More dht = exponentially more oxidative stress and a more pronounced hair loss on some locations, this is an oversimplification of the idea however)

Age related hair loss (senescent alopecia) goes trough the same pathway, follicles gets more sensible to DHT/oxidative stress over time.

 

[Swoop]

Well this is all kind of related.

DHT induces oxidative stress in the hair follicles -> cells are going senescent and stop to divides / inflammation -> hair loss

Bingo. This is the broad consensus among multiple research teams for Androgenetic Alopecia. I would call it androgens > AR though. Anyway if true, it's not pretty to say the least.

 

[abcdefg]

I'd guess they're two processes that can occur concurrently in males - on one hand, male pattern baldness, on the other, loss of hair from senescent stem cells. After all, even men who don't have male pattern baldness experience loss of hair density over their whole scalp as they age.

Is this really true? If I could find 1 man on earth that is alive now or ever existed that was 60 with zero or no noticeable loss in density than that would disapprove this statement. I dont agree that male pattern baldness is tied to aging because I have seen old men with no hair loss but its certainly rare. Visual evidence alone tells me its not aging. Every person I have ever seen at 60 has aged at a cellular level but having the hair still means its not a direct result of cellular aging because that doesnt skip over anyone.
I guess im saying male pattern baldness and age related thinning should not be distinguished between as being different processes. They are one in the same.

 

[hellouser]

if you are talking about hhag, than it did a lot.
it gave amazing result of full thickening and total stop of the loss, the only problem was that the result went away very quick after they stopped it, and ofcourse there us serious safety issue.

No it did not. The guys at SAGA were all arguing whether or not if it was working. That alone tells you the results arent conclusive.

Having said that, why is this thread still going knowing that it doesnt work?

 

[champpy]

who exactly were the people testing this Sonic Hedgehog out? Were they forum members or part of an actual study being conducted?

 

[stoicone]

No it did not. The guys at SAGA were all arguing whether or not if it was working. That alone tells you the results arent conclusive.

Having said that, why is this thread still going knowing that it doesnt work?

I WAS one of the people to try HHAG. It unequivocally had a positive effect. It did for at least three other trialist. I never heard from the fourth. The question wasn't whether there was a result, but whether it was a result that outweighed the potential risks associated with the drug.

Six months after HHAG my hair looked better than it has in many years. I attributed it to dutasteride at the time, but as my hair has regressed while on dutasteride since that time, I'm fairly certain it was from HHAG. The results don't persist long enough that you can just use it one off. I'm seriously considering doing just one more run of the drug to see.

So there you have it - don't listen to folks who don't know what the hell they are talking about. We also weren't exactly scientific about it. So even if it hadn't worked in a sample size of four, that really wouldn't mean much.

- - - Updated - - -

No it did not. The guys at SAGA were all arguing whether or not if it was working. That alone tells you the results arent conclusive.

Having said that, why is this thread still going knowing that it doesnt work?

We actually were not all arguing. SlowMoe was arguing that Jimbo's photos weren't good enough. Literally every other person disagreed with him. Two other trialist have both commented on how much they liked the drug.

 

[champpy]

Stoicone, is this drug available for purchase or were you part of a study? If purchasable, where might i find it?

 

[Saint-Loup]

WTF!!:doh:
This board is coming 15 years back!!
SHH had been studied and tested by scientists... and planned to be market by a big(huge) compagny : Procter & Gamble.
But the project had been given up since SHH can be dangerous (it promotes cancer risks).
Its name was Curis...

 

[Swoop]

BUM.

Just made a article about the hedgehog pathway; http://hairandscience.com/curis-and-the-hedgehog-pathway/.

It sparked my interest again after reading this study; http://www.ncbi.nlm.nih.gov/pubmed/23211596.

Cell cycle re-entry by cochlear supporting cells and/or hair cells is considered one of the best approaches for restoring hearing loss as a result of hair cell damage. To identify mechanisms that can be modulated to initiate cell cycle re-entry and hair cell regeneration, we studied the effect of activating the sonic hedgehog (Shh) pathway. We show that Shh signaling in postnatal rat cochleae damaged by neomycin leads to renewed proliferation of supporting cells and hair cells.

There is much more to read obviously about this pathway. As I explain it seems to have a rather big role in hair follicle biology. For instance you can look at the the side effects of vismodegib which can induce (persistent) alopecia. A very high percentage of people who go on vismodegib have to deal with alopecia. Vismodegib suppresses hedgehog signalling.

Nonetheless this also shows the problem with Androgenetic Alopecia. Some pathways might be implicated in Androgenetic Alopecia that simply can't be modulated or even tested because of (huge) safety concerns especially for something like hair loss which isn't life-threatening.

 

[c_super2]

BUM.

Just made a article about the hedgehog pathway; http://hairandscience.com/curis-and-the-hedgehog-pathway/.

It sparked my interest again after reading this study; http://www.ncbi.nlm.nih.gov/pubmed/23211596.



There is much more to read obviously about this pathway. As I explain it seems to have a rather big role in hair follicle biology. For instance you can look at the the side effects of vismodegib which can induce (persistent) alopecia. A very high percentage of people who go on vismodegib have to deal with alopecia.

Nonetheless this also shows the problem with Androgenetic Alopecia. Some pathways might be implicated in Androgenetic Alopecia that simply can't be modulated or even tested because of (huge) safety concerns especially for something like hair loss which isn't life-threatening.

Swoop, thanks for posting this.

However, IMO it doesn’t matter if SHH pathway causes cancer if it also causes hair growth and is implicated in many ailments. Researchers better get started researching this pathway and try to find ways to make it safe. It doesn’t make any sense to avoid the elephant in the room.

Do you believe researchers will do more research on SHH pathway now?

 

[hellouser]

Swoop, thanks for posting this.

However, IMO it doesn’t matter if SHH pathway causes cancer if it also causes hair growth and is implicated in many ailments. Researchers better get started researching this pathway and try to find ways to make it safe. It doesn’t make any sense to avoid the elephant in the room.

Do you believe researchers will do more research on SHH pathway now?

If I recall, one of the presentations at the hair congress touched on SHH... I should have it uploaded soon.

 

[Swoop]

@c_super2

The hedgehog pathway is definitely under research, we still have much to learn about it. There is much to read about this pathway not only related to hair follicle biology. Here is a nice review; http://dev.biologists.org/content/141/18/3445.

Growing evidence indicates that HH regulates diverse quiescent stem cell populations, but the exact roles that HH signaling plays in adult organ homeostasis and regeneration remain poorly understood. Here, we review recently identified functions of HH in modulating the behavior of tissue-specific adult stem and progenitor cells during homeostasis, regeneration and disease. We conclude that HH signaling is a key factor in the regulation of adult tissue homeostasis and repair, acting via multiple different routes to regulate distinct cellular outcomes, including maintenance of plasticity, in a context-dependent manner.

As you can see they mention about tissues like skin, muscle, bone etc..

The morphogen Sonic hedgehog (Shh) controls the growth of multipotent progenitor cells in many tissues, including limb, bone, and skin (Callahan and Oro, 2001; Ingham and McMahon, 2001; Taipale and Beachy, 2001).

Here is a old presentation of Curis that shows how they wanted to use molecules of the pathway for possible regeneration of some tissues;
https://www.wpi.edu/News/Conf/Molecular/Presentations/platika.pdf.

I get your point but apparently it does pose a problem. In the case of hedgehog signalling for instance we see that only molecules that reach testing stages are for diseases like cancer and they all suppress the SHH pathway as far as I can see. Curis for instance as you can see had more ideas for other ailments (activation of hedgehog pathway) but they eventually only proceeded with using/testing their molecule(s) for cancer (suppressing hedgehog pathway).

 

[Bukowski]

WTF!!:doh:
This board is coming 15 years back!!
SHH had been studied and tested by scientists... and planned to be market by a big(huge) compagny : Procter & Gamble.
But the project had been given up since SHH can be dangerous (it promotes cancer risks).
Its name was Curis...

Yep, I remember!

 

[wow-wow]

people already tried hhag and ti thicked their hair, but there is high risk in this, more than anything else i think.

 

[Swoop]

people already tried hhag and ti thicked their hair, but there is high risk in this, more than anything else i think.

Jup, I agree. But that's where the problem lies. You can only go so far, before you will be running in circles.

 

[wow-wow]

Jup, I agree. But that's where the problem lies. You can only go so far, before you will be running in circles.

yes ofcourse, but i realy don't know what we can do about it.

 

[Swoop]

@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;

- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828374/
- http://www.ncbi.nlm.nih.gov/pubmed/17989730
- http://www.ncbi.nlm.nih.gov/pubmed/18702626
- http://www.ncbi.nlm.nih.gov/pubmed/25647436
- http://www.papersearch.net/view/detail.asp?detail_key=27731029
- http://www.ncbi.nlm.nih.gov/pubmed/25778683
- 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?