Molecular basis of androgenetic alopecia: From androgen to paracrine mediators through dermal papilla.

Journal of Investigative Dermatology (2008) 128, 262–269; doi:10.1038/sj.jid.5700999; published online 26 July 2007
Dihydrotestosterone-Inducible Dickkopf 1 from Balding Dermal Papilla Cells Causes Apoptosis in Follicular Keratinocytes

Mi Hee Kwack1, Young Kwan Sung1, Eun Jung Chung1, Sang Uk Im1, Ji Seop Ahn1, Moon Kyu Kim1 and Jung Chul Kim1

1Department of Immunology, School of Medicine, Kyungpook National University, Daegu, Korea

Correspondence: Dr Young Kwan Sung or Dr Jung Chul Kim, Department of Immunology, School of Medicine, Kyungpook National University, 2-101 Dong-In-Dong, Chung-Gu, Daegu 700-422, Korea. E-mail: ysung@knu.ac.kr or jayckim@knu.ac.kr

Received 5 February 2007; Revised 28 May 2007; Accepted 4 June 2007; Published online 26 July 2007.
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Abstract

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.

CausticSymmetry wrote:act
However, one recently development is AR coactivator Hic-5/ARA55. Controlling this could be another way to default MPB.

^ Interesting stuff, I'm not sure if I took it from that study correctly but DHT activates or upregulates the Hic-5/ARA55? Would it be safe to say that it's more or less any irritation that could contribute to these cellular responses?

Also, I'm wondering what effect iodine has on progenitor cells.

^ Internally or Topically? Funkystumpfighter has shown some promise topically but it's a lot of work. Nano-silver and Copper Tri-peptides topically looks extremely promising though, going to experiment with it soon. Nid mentioned a while back trying to get his hands on the copper, wonder if he ever did... anyway here's some specs on the C-Tri-peptides.

"dermal fibroblasts treated with copper tripeptide secreted less TGF-beta1 than did controls, suggesting a possible clinical use for decreasing excessive scar formation"


"When injected into skin or applied to the skin’s surface, GHK-Cu activates the processes that remove scarred or damaged tissue and deposit new tissue. Francois Maquart and colleagues (Universite de Reims) have published several reports demonstrating the role GHK-Cu in wound healing.

- GHK-Cu acts as an inducer of the second phase of healing when skin remodeling processes remove scars and tissue debris while rebuilding healthy skin. (5-11)

- GHK-Cu concomitantly stimulates the degradation of existing collagen and synthesis of new collagen.

- At the molecular level, GHK-Cu aids the rebuilding of new skin by increasing angiogenesis, the production of m-RNA for collagen, elastin, proteoglycans, glycosaminoglycans and decorin, while simultaneously stimulating the m-RNA production of, and synthesis of, certain metalloproteinases and anti-proteases that clear damaged protein and remove scars. (10-12)

- In addition, GHK-Cu suppresses secretion of scar-forming TGF-beta-1 by fibroblasts. (13)

- GHK-Cu also acts indirectly as a chemoattractant for cells that stimulate repair, such as macrophages and mast cells, which release protein growth factor proteins that stimulate tissue repair. (6)

GHK-Cu also appears to function in humans as a circulating non-steroidal anti-inflammatory. (14) After episodes of tissue damage, ferric ion is released from ferritin and catalyzes damaging tissue oxidations. GHK- Cu counters this action by blocking ferritin channels and stopping the release of oxidizing iron ions. (15) GHK blocks the oxidation of low density lipoproteins by loosely bound copper. (16) Interleukin-1beta is also released after tissue injury producing cellular damage. At hormonal levels, GHK-Cu prevents damage to pancreatic cells by interleukin-1. (17)


- Stops inflammatory and scar-forming
- anti-inflammatory
- Inhibits TGF beta-1
- Suppresses Free Radicals
- Increases vasodilation
- Increases SOD
- Increases collagen and elastic
- Increases VEGF
- Increases Fibroblast Growth Factor-2
- Reduces fine lines, wrinkles, protects against UV damage, reduces UV damage
http://www.ncbi.nlm.nih.gov/pubmed/18644225

Is Copper Better Than Propecia(c) for Blocking DHT Production?

Recent research indicates that the DHT that harms hair follicles comes from the the skin's sebocytes and sweat glands (sebaceous glands). (Chen et al 1996) 5 alpha-Reductase, the enzyme system that converts testosterone into DHT occurs in two enzyme forms. The type 1 represents the 'cutaneous type'; it is located primarily in the skin's sebocytes but also in epidermal and follicular keratinocytes, dermal papilla cells and sweat glands as well as in fibroblasts. The type 2 is located mainly in the seminal vesicles, prostate and in the inner root sheath of the hair follicle.

Propecia(c) (Finasteride), which has a higher affinity for the type 2 form, is best suited for for controlling prostate enlargement. It also must be administered by pills that spread the drug throughout the body.

Copper ion in the skin is more effective in inhibiting the type 1 form which is primarily producing the DHT that damages follicles and can be administered locally to the skin. Sugimoto et al (Sugimito 1995) found that copper ion is a potent inhibitor of 5-alpha reductase, inhibiting both types of 5-alpha reductase (both type 1 and type 2) that produce DHT and is the only metal to do so. Copper ion inhibits (50% reduction in activity) type 1 alpha reductase at 1.9 micromolar (0.12 micrograms copper ion per milliliter) and type 2 alpha reductase at 19.2 microM (1.2 micrograms copper ion per milliliter). No other metal has these effects.

The application of copper-peptides may provide sufficient copper ion into the hair follicle area to block DHT production in the scalp. Metabolically active copper ion (that is, copper ion free to block 5-alpha reductase) in the human body exists at about 1 microgram per milliliter in the blood and less in the skin. While the uptake of ionic copper from copper-peptides applied to the scalp is very low, human experiments by Prof. John Sorenson (University of Arkansas) have found that they can raise copper ion levels in the skin to the effective level of 1 microgram per milliliter.

blueway wrote:What about using Catalyons (metal ions) topically ?

In vivo nano silver stem cell activation not only helps to dedifferentiate mature cells but also helps to provide larger numbers of progenitor cells from existing stem cells, including those obtained through dedifferentiation, ensuring highly accelerated healing and regeneration. In addition, this ability of nano-silver to stimulate all pre-existing stem cells to enhance the rate of production of progenitor cells results in an eventual regeneration of a fingertip in an unbelievably short time of 30 days. This is roughly five times faster than the unaided body really can achieve.

CausticSymmetry wrote:act
However, one recently development is AR coactivator Hic-5/ARA55. Controlling this could be another way to default MPB.

Also, I'm wondering what effect iodine has on progenitor cells.

The effect of tripeptide-copper complex on human hair growth in vitro.

Pyo HK, Yoo HG, Won CH, Lee SH, Kang YJ, Eun HC, Cho KH, Kim KH.

Department of Dermatology, College of Medicine, Seoul National University, Seoul 110-744, Korea.
Abstract

The tripeptide-copper complex, described as a growth factor for various kinds of differentiated cells, stimulates the proliferation of dermal fibroblasts and elevates the production of vascular endothelial growth factor, but decreased the secretion of transforming growth factor-beta1 by dermal fibroblasts. Dermal papilla cells (DPCs) are specialized fibroblasts, which are important in the morphogenesis and growth of hair follicles. In the present study, the effects of L-alanyl-L-histidyl-L-lysine-Cu2+ (AHK-Cu) on human hair growth ex vivo and cultured dermal papilla cells were evaluated. AHK-Cu (10(-12) - 10(-9) M) stimulated the elongation of human hair follicles ex vivo and the proliferation of DPCs in vitro. Annexin V-fluorescein isothiocyanate/propidium iodide labeling and flow cytometric analysis showed that 10(-9) M AHK-Cu reduced the number of apoptotic DPCs, but this decrease was not statistically significant. The ratio of Bcl-2/Bax was elevated, and the levels of the cleaved forms of caspase-3 and PARP were reduced by treatment with 10(-9) M AHK-Cu. The present study proposed that AHK-Cu promotes the growth of human hair follicles, and this stimulatory effect may occur due to stimulation of the proliferation and the preclusion of the apoptosis of DPCs.

act

blueway wrote:What about using Catalyons (metal ions) topically ?

Hey Blueway, is that question aimed at me? I think that the any ionic copper, especially copper tri-peptides and nano-silver possibly will have great results. I'm going to test it out.