Minoxidil activates β-catenin pathway in human dermal papilla cells: A possible explanation for its anagen prolongation effect.

J Dermatol Sci. 2011 Jun;62(3):154-9. Epub 2011 Feb 9.
Minoxidil activates β-catenin pathway in human dermal papilla cells: A possible explanation for its anagen prolongation effect.
Kwack MH, Kang BM, Kim MK, Kim JC, Sung YK.

Department of Immunology, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea.

BACKGROUND:
It is believed that the length of the actively growing phase of the anagen hair cycle mainly contributes to hair length. Recent studies showed that maintenance of β-catenin activity in the dermal papilla cells (DPCs) enables hair follicles to keep actively growing. Topical minoxidil treatment promotes hair growth in men with androgenetic alopecia, suggesting that minoxidil may prolong the actively growing phase of the anagen hair cycle.

OBJECTIVE:
To investigate whether minoxidil prolongs the anagen hair cycle in mice and, if so, to investigate whether minoxidil activates β-catenin pathway in human DPCs.

METHODS:
Dorsal skins of C57BL/6 mice were depilated to synchronize the hair cycle. After 10 days, 3% minoxidil were topically applied daily for 10 days. Sections of back skins were stained with hematoxylin and eosin. Hair follicles were graded and hair cycle score (HCS) was calculated. Cultured human DPCs were transiently transfected with the β-catenin responsive TCF reporter plasmid (pTopflash) and corresponding negative control reporter (pFopflash) to assess the activity of β-catenin signaling by minoxidil. Immunofluorescence staining and immunoblot were performed to examine the expression and localization of β-catenin in the presence or absence of minoxidil. Phosphorylation of GSK3β, PKA and PKB were also examined by immunoblot after minoxidil treatment. RT-PCR analysis and immunoblot were employed to investigate the expression of β-catenin pathway targets in DPCs, such as Axin2, Lef-1, and EP2.

RESULTS:
Modest extension of anagen phase thereby delay of catagen progression was observed by application of minoxidil in mice. Minoxidil stimulated the transcriptional activity of pTopflash but not pFopflash. Nuclear accumulation of β-catenin was also observed after minoxidil treatment. Immunoblot further showed that minoxidil treatment increases the phosphorylation of GSK3β, PKA and PKB. Moreover, minoxidil induced Axin2, Lef-1, and EP2 expression.

CONCLUSION:
Our results strongly suggest that minoxidil extends the anagen phase by activating β-catenin activity in the DPCs.

Naturally, there are better things than minoxidil, this only partially explains one of the mechanisms.

CS,

Do you know how this relates to previous studies showing that minoxidil prolongs anagen phase by activating sodium-potassium channels in the DP cells? More importantly, how can we activate the β-catenin pathway through natural means (simulate the effects of minoxidil)?

A related study:

Wnt signaling through the beta-catenin pathway is sufficient to maintain, but not restore, anagen-phase characteristics of dermal papilla cells.
Shimizu H, Morgan BA.
Source

Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Abstract

Dermal papilla cells of the hair follicle can be maintained in an active, hair-inducing state in vitro when cocultured with cells secreting Wnt3a. By inducing cultured dermal papilla cells to secrete Wnt themselves, we demonstrate that this activity is a direct effect of Wnt signaling to dermal papilla cells. We further demonstrate that the effects of Wnt3a are exerted through activation of the beta-catenin signal transduction pathway and do not require alternative Wnt transduction cascades. Once dermal papilla cells have lost hair-inducing properties in vitro, neither treatment with Wnt nor expression of a truncated and activating form of beta-catenin is sufficient to restore these properties to the cultured cells.

I think I remember something from other threads about DKK-1 inhibiting WNT signaling?

An abstract about altered WNT signaling in psoriatic skin:

Evidence for altered Wnt signaling in psoriatic skin.
Gudjonsson JE, Johnston A, Stoll SW, Riblett MB, Xing X, Kochkodan JJ, Ding J, Nair RP, Aphale A, Voorhees JJ, Elder JT.
Source

Department of Dermatology, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA. johanng@med.umich.edu
Abstract

The Wnt gene family encodes a set of highly conserved secreted signaling proteins that have major roles in embryogenesis and tissue homeostasis. Yet the expression of this family of important mediators in psoriasis, a disease characterized by marked changes in keratinocyte growth and differentiation, is incompletely understood. We subjected 58 paired biopsies from lesional and uninvolved psoriatic skin and 64 biopsies from normal skin to global gene expression profiling. WNT5A transcripts were upregulated fivefold in lesional skin, accompanied by increased Wnt-5a protein levels. Notably, WNT5A mRNA was markedly induced by IL-1alpha, tumor necrosis factor-alpha, IFN-gamma, and transforming growth factor-alpha in cultured keratinocytes. Frizzled 2 (FZD2) and FZD5, which encode receptors for Wnt5A, were also increased in lesional psoriatic skin. In contrast, expression of WIF1 mRNA, encoding a secreted antagonist of the Wnt proteins, was downregulated >10-fold in lesional skin, along with decreased WNT inhibitory factor (WIF)-1 immunostaining. Interestingly, pathway analysis along with reduced AXIN2 expression and lack of nuclear translocation of beta-catenin indicated a suppression of canonical Wnt signaling in lesional skin. The results of our study suggest a shift away from canonical Wnt signaling toward noncanonical pathways driven by interactions between Wnt-5a and its cognate receptors in psoriasis, accompanied by impaired homeostatic inhibition of Wnt signaling by WIF-1 and dickkopf.

The abstract is a little bit technical, but I believe that it's saying that psoriatic skin is characterized by increased levels of WNT proteins, but that signaling is suppressed anyway..perhaps due to a shortage of receptors? The last bit is interesting because it confirms that WNT signaling is inhibited by dickkopf (DKK).

I'm also quite interested in how we can activate the β-catenin pathway through natural diet/supplements, since minox has worked quite well for me in the past.

i second that. minox worked well for me. im hoping to reproduce the effect.

also, if we can replicate the effect through supplementation then people who are afraid to come off of minox due to the loss they'll endure can be more free to do so without the shed