Fgf and Wnt signaling interaction in the mesenchymal niche regulates the murine hair cycle clock

[pegasus2]

Could fgfr inhibitor + wnt agonist be conparable to shh agonist or is shh on a different level?

Shh is a signal that's required for morphogenesis, but dispensable for maintaining anagen. Wnts and Rspo2/3 are indispensable for maintaining anagen. High Wnt signaling during late wound-healing promotes fibrotic fate, and shh overrides that to promote DP fate and HF morphogenesis. I'm using an shh agonist PWD 5-8 for that purpose while trying to keep Wnt signaling high, and finally now I will have something to keep Rspo elevated.

 

[MrJolly26]

Great, then we will wait for the results! Thanks for sharing and good luck.

 

[BaldAndBalder]

That hairy mouse craked me up

 

[Armando Jose]

High levels of AR expression inhibit Wnt activity, which suppresses R-spondins, and the breakdown of this positive feedback loop causes Androgenetic Alopecia. We may be able to restore it by silencing the AR, upregulating Wnts, and silencing FGFR. We should all be thankful for cancer research, it wouldn't be possible for us to do this without it.

Wnts signal change during the normal hair cycle, our scalp hair is asynchronous (one hair in anagen and other in telogen), then what happen when we used a med affecting all hairs?
It is extrem complicated, ----, similar to your regime, but a lot of luck with your experimentation. Take care.

 

[Mandar kumthekar]

All these treatment would lead to cancer if the topical or drug gets into system.

 

[John Difool]

Shh is a signal that's required for morphogenesis, but dispensable for maintaining anagen. Wnts and Rspo2/3 are indispensable for maintaining anagen. High Wnt signaling during late wound-healing promotes fibrotic fate, and shh overrides that to promote DP fate and HF morphogenesis. I'm using an shh agonist PWD 5-8 for that purpose while trying to keep Wnt signaling high, and finally now I will have something to keep Rspo elevated.

I am using shh day 0 (pwd-1) till pwd 10

 

[lonelypanda]

You guys are out of your minds putting this sh*t on your heads, I really don't think it's a good idea long term. That being said, I'll be following your progress with great interest. God speed gentlemen.

 

[Equal Rights]

You guys are out of your minds putting this sh*t on your heads, I really don't think it's a good idea long term. That being said, I'll be following your progress with great interest. God speed gentlemen.

They are not doing it long term, just getting to the point they want to be at then maintaining using 5ARIs, AAs + maybe a few more

 

[Sweuser]

Hi pegasus,

Interesting read, as always!

I'm not sure if you have seen this, but with what you're trying to accomplish parallell, this might interfere?

FGF signaling is required for wnt driven ectopic HF initiation and involved in wound-induced hair neogenesis.

"Gene expression analysis of purified DS cells with activated β-catenin revealed significantly increased expression of Bmp, Fgf, and Notch ligands and administration of Bmp, Fgf, or Notch signaling inhibitor attenuates EF formation."

β-catenin activation in hair follicle dermal stem cells induces ectopic hair outgrowth and skin fibrosis

Abstract. Hair follicle dermal sheath (DS) harbors hair follicle dermal stem cells (hfDSCs), which can be recruited to replenish DS and dermal papilla (DP). Cul

academic.oup.com

Makes sense though, adverse event from Infigratinibe is eye brow hypertrichosis(extended anagen) but also listed is alopecia.

Thoughts?

 

[pegasus2]

@Sweuser It all depends on how much silencing FGFR upregulates RSPO2/3 and b-catenin. If it's more than fgf7 then no problem. I'm using a Smo agonist so I don't need fgf9 for morphogenesis, just Shh and Wnts.

 

[Sweuser]

@Sweuser It all depends on how much silencing FGFR upregulates RSPO2/3 and b-catenin. If it's more than fgf7 then no problem. I'm using a Smo agonist so I don't need fgf9 for morphogenesis, just Shh and Wnts.

Thanks!

I realized now you posted two articles and I think I follow you...

Do we know if FGF9 still have positive effect on HFs if Infigratinib is present? Is the positive effect only via Smoothened?

 

[pegasus2]

Thanks!

I realized now you posted two articles and I think I follow you...

Do we know if FGF9 still have positive effect on HFs if Infigratinib is present? Is the positive effect only via Smoothened?

FGF3/7/10 all positively regulate hair growth too. FGF5 is a negative regulator. In terms of morphogenesis FGF9 has a role in regulating Wnts and Shh. I'll let you know in a few months if Infigratinib sets me back or gives me a boost. I have 5g coming.

 

[Sweuser]

FGF3/7/10 all positively regulate hair growth too. FGF5 is a negative regulator. In terms of morphogenesis FGF9 has a role in regulating Wnts and Shh. I'll let you know in a few months if Infigratinib sets me back or gives me a boost. I have 5g coming.

Very interesting!

You probably saw the newly published paper on FGFRi and dermatological side effects associated.

Error - Cookies Turned Off

theoncologist.onlinelibrary.wiley.com

They also proposed an absolute contraindication for continuing treatment.

Good luck!

 

[pegasus2]

Very interesting!

You probably saw the newly published paper on FGFRi and dermatological side effects associated.

Error - Cookies Turned Off

theoncologist.onlinelibrary.wiley.com

They also proposed an absolute contraindication for continuing treatment.

Good luck!

Thanks! It's contradictory. Eyelash growth, but scalp alopecia. The other FGFRi's also inhibit VEGFR, while Infigratib does not at low doses. Unsurprisingly, alopecia is a less common side effect in Infigratinib versus the others.

 

[pegasus2]

Severe onycholysis and eyelash trichomegaly in a patient treated with erdafitinib

www.ncbi.nlm.nih.gov

Because of the known FGFR3 mutation, erdafitinib was initiated. The patient experienced abrupt relief of urinary symptoms and cancer-related pain; however, 8 weeks after therapy initiation he complained of nail, skin, and hair changes and was referred to the dermatology department. On examination, there was near-complete onycholysis of all fingernails and toenails with complete loss of 1 nail plate. Additional nail changes include malodorous, purulent drainage from multiple fingernails and paronychia (Fig 1). Hair changes included coarsening and curling of scalp hair, eyebrow hypertrichosis, and eyelash trichomegaly

Erdafitinib is a FRFR1-4 inhibitor. I could do without curling, but coarsening of scalp hair is what we are aiming for.

 

[InBeforeTheCure]

Severe onycholysis and eyelash trichomegaly in a patient treated with erdafitinib

www.ncbi.nlm.nih.gov

Erdafitinib is a FRFR1-4 inhibitor. I could do without curling, but coarsening of scalp hair is what we are aiming for.

That looks similar to FGF5 mutation effects, less extreme though. (source)

 

[pegasus2]

That looks similar to FGF5 mutation effects, less extreme though. (source)

FGF5 inhibition is the safer option if anyone figures out which compound is MTP3.

Promotion of anagen, increased hair density and reduction of hair fall in a clinical setting following identification of FGF5-inhibiting compounds via a novel 2-stage process

There are very few effective, scientifically validated treatments with known mechanisms of action for treatment of hair loss in both men and women. Fibroblast growth factor 5 (FGF5) is an important factor in the irreversible transition from anagen to ...

www.ncbi.nlm.nih.gov

Unfortunately it isn't just FGF5.

Fgf5 function is relayed to the DP through activation of other Fgf ligands in the matrix that trigger Fgf transduction in the DP. However, anagen in the Fgf5 knockout mice is extended by 3 days22 while ablation of Fgfr1 and Fgfr2 in the DP results in anagen extension between 6 and 8 days. This suggests that a combined action of a few Fgf ligands is involved. Consistently, several Fgf ligands are known to be expressed during anagen in both the epithelial compartment and the DP28. Future functional analysis of these ligands will decipher their role in this process and dissect their relative contribution.

 

[John Difool]

Just ordered Infigratinib. Lets do it,

 

[Selb]

Just ordered Infigratinib. Lets do it,

Keep us posted dude

 

[polishkickbuttowski]

FGF5 inhibition is the safer option if anyone figures out which compound is MTP3.

Promotion of anagen, increased hair density and reduction of hair fall in a clinical setting following identification of FGF5-inhibiting compounds via a novel 2-stage process

There are very few effective, scientifically validated treatments with known mechanisms of action for treatment of hair loss in both men and women. Fibroblast growth factor 5 (FGF5) is an important factor in the irreversible transition from anagen to ...

www.ncbi.nlm.nih.gov

Unfortunately it isn't just FGF5.

Is this quote comparing inhibition of fgfr5 to inhibition of fgfr1&2 or inhibition of fgfr1&2&5?