Dickkopf vs TGF-Beta

[docj077]

Michael,

Just as the hormonal profile in mice is dissimilar to that of humans, so is the possibility that similar mechanisms related to hair follicle generation are unequivicable, as well.

Remember, it only takes ONE blistering sunburn to DOUBLE your risk of developing malignant melanoma. Imagine what can happen with disregulating this system even once. Researchers wouldn't know if it causes cancers, because it often takes decades in humans to see the development of melanoma and I can guarantee that such a product will be rushed to market.

We're talking about a system that is in contant state of rapid turnover and regeneration.

Besides, I'm not concerned with the dermabrasion procedure. I'm referring to rantings of earlier posters. To be honest, I'm not surprised that such a procedure works. What I'm concerned with are those that think they can interrupt or even increase intracellular signaling processes related to Wnt signaling through injectable or internal means. Even using such products topically is ill-advised.

 

[michael barry]

Doctor,

Your points are well-considered, and long-term effects are at least a externality that warrants thinking. Ive had a couple of blistering sunburns in my life. Its something Ive worried about myself.



However, I will remind you that they have grown human hair on human skin in experiments, so we know, at least on human skin grafted onto a SCID mouse, this procedure (Epidermal Disruption Inducing Hair Follicle Neogenesis) or EDIFHN as they refer to it in the patent, can work in a human being. The only thing that would stop it from transferring from mice to men is the human immune system having a trick up its sleeve.


The only problem I have with their human skin example was that is was skin obtained from a hair transplant clinic, so its the "donor area" skin. We are concerned with the recipient area being able to grow hair. The fact that balding skin in the frontal scalp has lost a water layer and a fatty acid layer might alter any neo-genesis taking place up there.



They have recruited for their first trial, so we will know shortly whether it works up front or not. Im hoping that it at least works well in the back to make more hair available for transplantation.

 

[harold]

Messing with cellular signaling pathways that are as tightly controlled as the Wnt signaling pathway (ie inhibiting DKK1 function) is fruitless and naive on the part of those that even attempting it. The potential damage that such pharmacological or procedural inventions could have on the human body will be both deadly and unforgivable.

I disagree - done in a localised and controlled manner I dont see the problem. Research seems to indicate that androgens are messing with such tightly controlled signalling pathways on both of our heads even as we speak.
hh

You don't see the problem, because you don't understand the significance. You do not have to maintain DKK1 inhibition for long periods of time in order to disregulate the system. All it takes the removal of such an inhibitory signal for even a short amount of time to kick even one cell into a pro-proliferative state.

Yes. This is exactly the point. And thats what we are trying to achieve.

This bullcrap that everyone doing this research is saying about the process being short-lived, intermittent, etc. is going to come back to bite them all in the ***. The reason this worksd for androgens for prolonged periods is because they maintain the tightly controlled system in the form of negative regulators.

Of course there is less risk of tumour formation when you are inhibiting cell proliferation. Theres less risk of tumour formation when you are dead. But if you want to live and you want to have things like hair and skin and dividing cells then that is a risk you are going to have to take. Tumour like cysts developed when the wnt pathway was hit hard and for a long period of time (and resolved upon cessation of that signal). When it was hit intermittently it simply produced more hair. I really dont think its going to be any different in humans.

Also, simply upregulating Wnt signaling will likely not regrow hair in everyone.

What does?

Case and point is the recent study out of Stanford that demonstrated that the Wnt signaling pathway can have a negative effect on stem cell function. According to their research, inhibition of the pathway may be a therapeutic target to help slow aging and increase healing.

Thats because wnt signalling helps to determine what type of cell a stem cell will become. In the skin it influences that cell to become a hair follicle. If you deplete the stem cell population by constantly signalling those cells to go off and become something else then thats a bad thing obviously. I dont really see this as relevant. Nobody has proposed that upregulating wnt signalling throughout the human body indefinitely is a good thing. They havent even proposed doing it on the scalp all the time. One of the things we now know is that timing in these things is everything. Mice which cant express BMPs in the skin go bald after their first hair cycle. BMPs which are antiproliferative. Which are a negative regulator of hair follicle size. But also a necessary part of the hair follicle cycle of anagen, catagen, telogen. We have come beyond "x = good, y = bad" and these guys are very aware of that.

Why do these guys get a free pass for proposing to inhibit wnt signalling? Because they want to inhibit at and not activate it? I dont see that taking control of a process that is being run in a direction that we dont want it to by blind random forces is necessarily going to lead to doom and gloom. If I thought there was a reason that people were not meant to have hair on their heads after 25 I might reconsider. But as the existance of women and non-balding people in general shows that doesnt seem to be the case.
hh

 

[bornthisway]

More on dickkopf 1

Dihydrotestosterone-inducible dickkopf 1 from balding dermal papilla cells causes apoptosis in follicular keratinocytes.

Recent studies suggest that androgen-driven alteration to the autocrine and paracrine factors produced by scalp dermal papilla (DP) cells may be a key to androgen-potentiated balding. Here, we screened dihydrotestosterone (DHT)-regulated genes in balding DP cells and found that dickkopf 1 (DKK-1) is one of the most upregulated genes. DKK-1 messenger RNA is upregulated in 3-6 hours after 50-100 nM DHT treatment and ELISA showed that DKK-1 is secreted from DP cells in response to DHT. A co-culture system using outer root sheath (ORS) keratinocytes and DP cells showed that DHT inhibits the growth of ORS cells, and neutralizing antibody against DKK-1 significantly reversed the growth inhibition of ORS cells. Analysis of co-cultured ORS cells showed a significant increment of sub-G1 apoptotic cells in response to DHT. Also, recombinant human DKK-1 inhibited the growth of ORS cells and triggered apoptotic cell death. In addition, DHT-induced epithelial cell death in cultured hair follicles was reversed by neutralizing DKK-1 antibody. Moreover, immunoblotting showed that the DKK-1 level is up in the bald scalp compared with the haired scalp of patients with androgenetic alopecia. Altogether, our data strongly suggest that DHT-inducible DKK-1 is involved in DHT-driven balding.

PMID: 17657240 [PubMed - indexed for MEDLINE]

 

[joemadrid]

Have found this about

Dickkopf-1 protein secretion was documented in breast, prostate and lung cancer lines, but was negligible in melanoma.