Dickkopf vs TGF-Beta

[harold]

This is something that I am waiting for - a while a go there was an epublication of a study that identified dickkopf-1 (an inhibitor of the wnt pathway - see the thread on wounds and new hair follicle development) as one of the/the most upregulated genes following exposure of the dermal papillae to DHT. TGF-Beta has been known for a while now to be an autocrine/paracrine messenger secreted in response to DHT by balding cells. Both seem to trigger apoptosis of follicles, TGF-Beta seems to promote the deposition of collagen in the scalp and thus play a part in fibrosis and is possibly involved in oxidative stress of the follicles. Dickkopf as a wnt inhibitor may interfere with the hair follicles transition to anagen.
In that study they mentioned a table that listed the 30 genes most highly upregulated by DHT - and yet it is not (yet) included in the paper as available online. I am very curious to see this tabel and see if TGF-beta transcription was one of the things they looked at or if they picked dickkopf from another group of senes/proteins. A look at the relative upregulation of each gene might give a better idea of which is the more "important factor" in male pattern baldness. Though TGF-Beta is more familiar to most of us the new research on the role of wnt in the development of new follicles makes dickkopf seem a lot more interesting than as just another inhibitory factor. Of course the truth is amost certainly that both are important amongst other secondary inhibitory factors downregulated and growth factors upregulated. Still....I would love to see that table.
hh

 

[mumuka]

The top 30 upregulated genes in balding dermal papilla cells in response to 100 nM DHT determined by microarray hybridization.


Gene Genebank ID Fold increase

tyrosyl-tRNA synthetase (YARS) NM_003680 5.07

dickkopf homolog 1 (DKK1) NM_012242 4.64

serum/glucocorticoid regulated kinase (SGK) NM_005627 4.53

a disintegrin-like and metalloprotease (ADAMTS5) NM_007038 3.75

solute carrier family 19 (SLC19A2) NM_006996 3.31

solute carrier family 2 (SLC2A3) NM_006931 2.99

H2A histone family, member Z (H2AFZ) NM_002106 2.86

RING1 and YY1 binding protein (RYBP) NM_012234 2.75

nuclear receptor coactivator 3 (NCOA3) NM_181659 2.63

adenosylmethionine decarboxylase 1 (AMD1) NM_001634 2.46

LPS-induced TNF-alpha factor (LITAF) NM_004862 2.36

ornithine decarboxylase 1 (ODC1) NM_002539 2.34

myeloid cell leukemia sequence 1 (MCL1) NM_182763 2.32

ATPase family homolog up-regulated in senescence cells (AFURS1) NM_024524 2.31

ADP-ribosylation factor-like 4C (ARL4C) NM_005737 2.3

cyclin-dependent kinase inhibitor 1A (p21) (CDKN1A) NM_000389 2.3

aldo-keto reductase family 1, member C1 (AKR1C1) NM_001353 2.29

DEAD (Asp-Glu-Ala-Asp) box polypeptide 5 (DDX5) NM_004396 2.27

fibroblast growth factor 7 (FGF7) NM_002009 2.26

solute carrier family 3 (SLC3A2) NM_002394 2.22

VAMP-associated membrane protein B (VA0AP) NM_003574 2.1

HSPC048 protein (HSPC048) NM_014148 2.09

syndecan binding protein (syntenin) (SDCBP) NM_005625 2.08

matrix metalloproteinase 3 (MMP3) NM_002422 2.08

cyclin-dependent kinase inhibitor 1A (p21) (CDKN1A) NM_078467 2.07

Kruppel-like factor 10 (KLF10) NM_005655 2.02

heme oxygenase (decycling) 1 (HMOX1) NM_002133 2.02

UDP-glucose ceramide glucosyltransferase (UGCG) NM_003358 2.01

solute carrier family 7 (SLC7A5) NM_003486 1.99

transforming growth factor, beta 2 (TGFB2) NM_003238 1.98

 

[michael barry]

good stuff Mumka

 

[docj077]

If you go through all of them and research the function of each one a rather interesting picture develops. What you have is a plethora of molecules associated with an inflammatory response; be it endothelial or epithelial in origin. What you also have is a wide array of molecules associated with establishing a pro-apoptotic environment, as well as, a pro-fibrotic environment.

On the other hand, there are also a few molecules upregulated in there that are clearly pro-growth. It really does look as though the body is trying to upregulate growth, but it simply can't overcome all the negative growth signals.

Definitely a good post.

 

[harold]

Well - thanks Mumuka! Glad I made this post. Also a little confused as to why I cant see the table myself in the Supplementary section. It says "Table S1. The top 30 upregulated genes in balding dermal papilla cells in response to 100 nM DHT determined by microarray hybridization." but then there is nothing. Perhaps it is a firefox/IE thing.

Anyway. It seems that Dickkopf is way ahead as the number 2 most upregulated gene while TGF-Beta-2 comes in at number 30 with about half as much extra RNA produced after DHT does its thing. TGF-Beta 1 is presumably somewhat less upregulated. Then again according to one poster presentation that has yet to find its way into publication form dht causes the generation of oxidative species that then go onto trigger TGF-Beta release. But not going into the methods used in the study I would think that would still be included in whatever the figure for the increase in the transcription of TGF-Beta 1 is.

Docj007 would you be able to give us a short rundown on some of what you see as the major players and how they fit together based on this list of suspects? I am prob not as familiar with the proinflammatory modulators as I have never been a big believer in that side of the hairloss thing. Not saying its not there - just that not much seems to have come of people using some pretty strong, even dangerous, anti-inflammatories on there scalps. Though I must say when not on finasteride or some form of antiandrogen i do feel that widely reported itch/pain in the thinning areas and from photos they seem to be somewhat reddened/inflamed. Would be tempted to put it down to placebo except there was a study that found that more men suffering male pattern baldness had these symptoms than otherwise. At any rate I was thinking of putting up a topic to debate the role of inflammation in hairloss where those who thought it important and those who thought it was of little or no importance could put their views and reasoning. Could be interesting.

Thank God for microarray technology. It really shows us a whole new world of stuff beyond DHT that we can now begin to understand.

Lastly - what do we know if anything about antagonising Dickkopf?
hh

 

[jakeb]

From http://www.hairsite.com/hair-loss/board ... p?id=14952:

Possible DKK1 inhibitors:
1. R-Spondin1 (aka NU206): a new product which is being marketed by a company called Nuevlo for gastrointestinal cancer; still in Phase I trials so not currently available; but shown to have inhibitory effects on DKK1.
http://www.pnas.org/cgi/content/full/104/37/14700

2. Bortezomib: anti-cancer drug; must be taken intravenously and may have significant side-effects (e.g., neuropathy); but shown to reduce serum concentrations of DKK1.
http://www.ingentaconnect.com/content/b ... 5/art00013

3. Lithium: upregulates WNT pathway (i.e., it upregulates Bax and suppresses Bcl-2, neutralizing GSK-3b); lithium also has many positive functions on inflammation and reducing sebum production (it's more effective than ketoconazole for seborrheic demratitis). I haven't seen anything on DKK1 inhibition but it might be effective, no?
http://www.freepatentsonline.com/20050084494.html

4. DMSO: boosts WNT signaling, beta-catenin, and increases absorption of lithium as a nice bonus. I haven't seen any research on DKK1 inhibition, though.

 

[harold]

From http://www.hairsite.com/hair-loss/board ... p?id=14952:

Possible DKK1 inhibitors:
1. R-Spondin1 (aka NU206): a new product which is being marketed by a company called Nuevlo for gastrointestinal cancer; still in Phase I trials so not currently available; but shown to have inhibitory effects on DKK1.
http://www.pnas.org/cgi/content/full/104/37/14700

2. Bortezomib: anti-cancer drug; must be taken intravenously and may have significant side-effects (e.g., neuropathy); but shown to reduce serum concentrations of DKK1.
http://www.ingentaconnect.com/content/b ... 5/art00013

3. Lithium: upregulates WNT pathway (i.e., it upregulates Bax and suppresses Bcl-2, neutralizing GSK-3b); lithium also has many positive functions on inflammation and reducing sebum production (it's more effective than ketoconazole for seborrheic demratitis). I haven't seen anything on DKK1 inhibition but it might be effective, no?
http://www.freepatentsonline.com/20050084494.html

4. DMSO: boosts WNT signaling, beta-catenin, and increases absorption of lithium as a nice bonus. I haven't seen any research on DKK1 inhibition, though.

Lithium may be a little hard to acquire....and hair thinning is a common side effect on oral doses although documented changes in hair texture/type on lithium are interesting
"Acta psychiatr. scand. 1985:72:387-388
Lithium and hair texture
R. G. McCreadie and J. G. Farmer
ABSTRACT - Patients receiving lithium who had noticed changes in hair texture
since starting that drug, described variously as hair losing its curl or wave, have a
greater lithium concentration in hair than patients on lithium with no such
complaints."

On the other hand the DMSO one is very interesting especially considering the reputation that MSM has acquired and the similarity between the two substances.
hh

A Wnt- and beta -catenin-dependent pathway for mammalian cardiac myogenesis.
Nakamura T, Sano M, Songyang Z, Schneider MD.

Center for Cardiovascular Development and Department of Biochemistry, Baylor College of Medicine, Houston, TX 77030, USA.

Acquisition of a cardiac fate by embryonic mesodermal cells is a fundamental step in heart formation. Heart development in frogs and avians requires positive signals from adjacent endoderm, including bone morphogenic proteins, and is antagonized by a second secreted signal, Wnt proteins, from neural tube. By contrast, mechanisms of mesodermal commitment to create heart muscle in mammals are largely unknown. In addition, Wnt-dependent signals can involve either a canonical beta-catenin pathway or other, alternative mediators. Here, we tested the involvement of Wnts and beta-catenin in mammalian cardiac myogenesis by using a pluripotent mouse cell line (P19CL6) that recapitulates early steps for cardiac specification. In this system, early and late cardiac genes are up-regulated by 1% DMSO, and spontaneous beating occurs. Notably, Wnt3A and Wnt8A were induced days before even the earliest cardiogenic transcription factors. DMSO induced biochemical mediators of Wnt signaling (decreased phosphorylation and increased levels of beta-catenin), which were suppressed by Frizzled-8Fc, a soluble Wnt antagonist. DMSO provoked T cell factor-dependent transcriptional activity; thus, induction of Wnt proteins by DMSO was functionally coupled. Frizzled-8Fc inhibited the induction of cardiogenic transcription factors, cardiogenic growth factors, and sarcomeric myosin heavy chains. Likewise, differentiation was blocked by constitutively active glycogen synthase kinase 3beta, an intracellular inhibitor of the Wntbeta-catenin pathway. Conversely, lithium chloride, which inhibits glycogen synthase kinase 3beta, and Wnt3A-conditioned medium up-regulated early cardiac markers and the proportion of differentiated cells. Thus, Wntbeta-catenin signaling is activated at the inception of mammalian cardiac myogenesis and is indispensable for cardiac differentiation, at least in this pluripotent model system.

 

[dopey]

viewtopic.php?f=32&t=39674

I had posted this earlier but it didn't get much discussion.

Lithium Chloride and lithium oratate can be obtained very easily. There are more than a few people trying this over at regrowth. You can also purchase a pre-made topical lithium gel.

 

[harold]

Wow all the way back in August eh?
Will be interesting to see what the results of the lithium are.
hh

 

[S Foote.]

If you go through all of them and research the function of each one a rather interesting picture develops. What you have is a plethora of molecules associated with an inflammatory response; be it endothelial or epithelial in origin. What you also have is a wide array of molecules associated with establishing a pro-apoptotic environment, as well as, a pro-fibrotic environment.

On the other hand, there are also a few molecules upregulated in there that are clearly pro-growth. It really does look as though the body is trying to upregulate growth, but it simply can't overcome all the negative growth signals.

Definitely a good post.

http://www.ncbi.nlm.nih.gov/entrez/quer ... s=16834456

S Foote.

 

[dopey]

Wow all the way back in August eh?
Will be interesting to see what the results of the lithium are.
hh

There are a few guys having good results, hatchet, librarian and immortalhair. As a Norwood 5, hatchet has grown "hundreds" of new terminal hairs.

 

[abcdefg]

This stuff is over my head, but it fills me with confidence that we have people that know things in this much detail and stay on top of all the newest research. I do think we are really starting to figure out how male pattern baldness works much more so then any time in history.
I get that bad itch and I think my hairloss is absolutely related to that as my hair miniaturizes right where it itches. I think i have low amounts of dht so my hair loss is very slow luckily. I dont need to know anything to say the immune system is involved because I have bad acne only right where hair is starting to miniaturize and no where else.

 

[docj077]

If you go through all of them and research the function of each one a rather interesting picture develops. What you have is a plethora of molecules associated with an inflammatory response; be it endothelial or epithelial in origin. What you also have is a wide array of molecules associated with establishing a pro-apoptotic environment, as well as, a pro-fibrotic environment.

On the other hand, there are also a few molecules upregulated in there that are clearly pro-growth. It really does look as though the body is trying to upregulate growth, but it simply can't overcome all the negative growth signals.

Definitely a good post.

http://www.ncbi.nlm.nih.gov/entrez/quer ... s=16834456

S Foote.

.."increase in the number and size of microlymphatic structures in the lymphedematous cutaneous tissues"

"acute post-surgical lymphedema in the tails of female hairless, immunocompetent SKH-1 mice"

"In the mouse tails that had had their lymph vessels damaged, the authors were able to show that the tails were swollen compared with those of normal animals and of animals that hadhad sham (pretend) surgery. In the animals with lymphedema, many small lymph vessels were seen, as the lymph was unable to flow away normally"

"There was a notable increase in cellularity, with an increase in the number of observed fibroblasts and histiocytes, as well as a large infiltration of neutrophils Granulation tissue was observed closer to the center of the section, with bystander destruction of muscle tissue. In addition, there was hyperkeratosis and spongiosis and edema of the epidermis, with irregularity of the epidermal/dermal junction, elongation of the dermal papillae, and a 2- to 3-fold expansion of tissue between the bone and the epidermis. Lymphedema specimens were characterized by the presence of numerous dilated lymphatics in the dermis and subdermis, as seen in Figure 2B."


There are at least two genes that upregulated in a similar manner with regards to lymphedema and hair loss if you go through what has been posted here and the tables that they give in the study that demonstrate the upregulation and downregulation of specific genes. Unfortunately, those genes don't even make the top five for hair loss. Heme oxygenase is one and TGF-beta2 is the other. Both are expected to be upregulated in any inflammatory process, so one can not make a conclusion either way.

Another problem with this study is that a good researcher would realize that you can not compare acute disease to chronic disease. In the study you posted, they physically induced a lymphedematous reaction surgically in an acute manner. There was clear swelling, as well as, clear histological changes demonstrating what the researchers viewed throughout their experiments. male pattern baldness does not demonstrate the same histological characteristics. Hyperkeratosis can sometimes be visualized in male pattern baldness, but spongiosis and edema are rarely seen. An inflammatory infiltrate is also a rarity at the microscopic level. I have never seen evidence for dilated lymphatic vessels or lymphatic vessel hyperplasia. Lastly, bystander muscle destruction is unheard of in androgenic alopecia.

The majority of the inflammation in male pattern baldness is confined to the infundibulum. It is not trans-epithelial, nor is it muscle destroying.


I can see how the two process would seem both similar and confusing to you.

 

[michael barry]

Interesting, but female mouse tails dont have hair. If you could show some hair was lost on the coats of mice like this.....................................well, you'd be onto something

We studied an experimental model of acute post-surgical lymphedema in the tails of female hairless, immunocompetent SKH-1 mice. We performed in vivo imaging of impaired immune traffic in experimental, murine acquired lymphatic insufficiency. We demonstrated impaired mobilization of immunocompetent cells from the lymphedematous region. These findings correlated with histopathological alterations and large-scale transcriptional profiling results. We found intense inflammatory changes in the dermis and the subdermis. The molecular pattern in the RNA extracted from the whole tissue was dominated by the upregulation of genes related to acute inflammation, immune response, complement activation, wound healing, fibrosis, and oxidative stress response. CONCLUSIONS: We have characterized a mouse model of acute, acquired lymphedema using in vivo functional imaging and histopathological correlation. The model closely simulates the volume response, histopathology, and lymphoscintigraphic characteristics of human acquired lymphedema, and the response is accompanied by an increase in the number and size of microlymphatic structures in the lymphedematous cutaneous tissues. Molecular characterization through clustering of genes with known functions provides insights into processes and signaling pathways that compose the acute tissue response to lymph stagnation. Further study of genes identified through this effort will continue to elucidate the molecular mechanisms and lead to potential therapeutic strategies for lymphatic vascular insufficiency.

 

[harold]

Wow all the way back in August eh?
Will be interesting to see what the results of the lithium are.
hh

There are a few guys having good results, hatchet, librarian and immortalhair. As a Norwood 5, hatchet has grown "hundreds" of new terminal hairs.

That sounds promising. But with most of these things time is the best judge. I noticed over at the regrowth forums one guy who had returned having tried the lithium topical years ago. He said he used a high concentration to be sure he wasn't underdoing it. After a while he noticed these pimple like lumps under the hairline he got scared and he stopped the treatment. The lumps went away and he lost some terminal hairs in the region that did not return. That made me think of this study:

"Development. 2004 Apr;131(8):1787-99.
Transient activation of beta-catenin signalling in adult mouse epidermis is sufficient to induce new hair follicles but continuous activation is required to maintain hair follicle tumours.
Lo Celso C, Prowse DM, Watt FM.

Keratinocyte Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.

When beta-catenin signalling is disturbed from mid-gestation onwards lineage commitment is profoundly altered in postnatal mouse epidermis. We have investigated whether adult epidermis has the capacity for beta-catenin-induced lineage conversion without prior embryonic priming. We fused N-terminally truncated, stabilised beta-catenin to the ligand-binding domain of a mutant oestrogen receptor (DeltaNbeta-cateninER). DeltaNbeta-cateninER was expressed in the epidermis of transgenic mice under the control of the keratin 14 promoter and beta-catenin activity was induced in adult epidermis by topical application of 4-hydroxytamoxifen (4OHT). Within 7 days of daily 4OHT treatment resting hair follicles were recruited into the hair growth cycle and epithelial outgrowths formed from existing hair follicles and from interfollicular epidermis. The outgrowths expressed Sonic hedgehog, Patched and markers of hair follicle differentiation, indicative of de novo follicle formation. The interfollicular epidermal differentiation program was largely unaffected but after an initial wave of sebaceous gland duplication sebocyte differentiation was inhibited. A single application of 4OHT was as effective as repeated doses in inducing new follicles and growth of existing follicles. Treatment of epidermis with 4OHT for 21 days resulted in conversion of hair follicles to benign tumours resembling trichofolliculomas. The tumours were dependent on continuous activation of beta-catenin and by 28 days after removal of the drug they had largely regressed. We conclude that interfollicular epidermis and sebaceous glands retain the ability to be reprogrammed in adult life and that continuous beta-catenin signalling is required to maintain hair follicle tumour"

Its possible that lithium is so potent a stimulator of this pathway that continuous "pinging" of it in strong doses is enough to not only develop new follicles but to turn them into tumourous growths. Some quick browsing of pubmed has given me the impression that wnt/dickkopf expression is a well ordered balance between growth stimulation and inhibition. On the one hand if the wnt/dickkopf ratio gets too low then it seems we get androgenetic alopecia. On the other it is well known/suspected that apoptosis and cell ular obsolescence are necessary to keep the development of cancerous cells under control. There seems to be a balancing act between ageing in general on the one hand and tendency to cancer on the other. Anyway enough speculation. At least of that kind. Not trying to "freak anyone out" who is trying the lithium treatment. If indeed it is THAT powerful at promoting trichogenesis then it should be easy enough to scale it back a bit and get excellent results.

Dopey do you have any other references for DMSO and its promotion of wnt signalling? I could only come up with a little as I posted before. I am actually thinking of starting an MSM topical but although similar to DMSO structurally it would be anyones guess I suppose if it actually has an effect on wnt signalling. But I just cant help but be intrigued by this new link between its so far purely anecdotal reputation as a hair growth stimulant and this DMSO/wnt thing.
hh

 

[dopey]

Harold,

I'll see what I can find.

By the way, the poster you mentioned is the esteemed "Fred102" aka sinere-advisor. Fred is a long time hair researcher.

 

[docj077]

By the way, Losartan, an angiotensin II receptor blocker, has been shown to reduce plasma levels of TGF-beta by up to fifty percent. It is demonstrated efficacy in patients with Marfan's Syndrome (the fibrillin defect prevents adequate TGF-beta binding) and Duchanne's Muscular dystrophy (the drug has been proven to reverse muscle wasting secondary to TGF-beta action).

Also, spironolactone has been shown to decrease TGF-beta in serum, as well as, reactive oxygen species concentrations thought the inhition of aldosterone mediated cellular processes.

As for Dickkopf-1, there has to be a reason why a tumor suppressor is being upregulated to reduce the function of the Wnt/B-catenin pathway.

 

[harold]

Just when you think it all might begin to make sense....

"SMAD7 or Mothers against decapentaplegic homolog 7 is a polypeptide that, as its name describes, is a homolog of the Drosophila gene: "Mothers against decapentaplegic". It belongs to the SMAD family of proteins, which belong to the TGF? superfamily of ligands. Like many other TGF? family members SMAD7 is involved in cell signalling. It is a TGF? type 1 receptor antagonist. It blocks TGF?1 and activin associating with the receptor and blocking access to SMAD2. It is an inhibitory SMAD (I-SMAD) and is enhanced by SMURF2."

Smad7: licensed to kill beta-catenin.
Millar SE.

Department of Dermatology, University of Pennsylvania, M8D Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, 19104, USA.

Elevated levels of inhibitory Smad7 are detected in several pathologic skin conditions; however the functional consequences of this expression have been unclear. A recent study shows that Smad7 overexpression in transgenic mouse epidermis at levels comparable to those seen in pathologic states is insufficient to block TGFbeta or BMP signaling, but instead produces striking phenotypes due to degradation of beta-catenin through a novel mechanism involving Smad7 and Smurf2.

Dev Cell. 2006 Sep;11(3):301-12.
Smad7-induced beta-catenin degradation alters epidermal appendage development.
Han G, Li AG, Liang YY, Owens P, He W, Lu S, Yoshimatsu Y, Wang D, Ten Dijke P, Lin X, Wang XJ.

Department of Otolaryngology, Oregon Health & Science University, Portland, 97239, USA.

To assess whether Smad signaling affects skin development, we generated transgenic mice in which a Smad antagonist, Smad7, was induced in keratinocytes, including epidermal stem cells. Smad7 transgene induction perturbed hair follicle morphogenesis and differentiation, but accelerated sebaceous gland morphogenesis. Further analysis revealed that independent of its role in anti-Smad signaling, Smad7 bound beta-catenin and induced beta-catenin degradation by recruiting an E3 ligase, Smurf2, to the Smad7/beta-catenin complex. Consequently, Wnt/beta-catenin signaling was suppressed in Smad7 transgenic hair follicles. Coexpression of the Smurf2 and Smad7 transgenes exacerbated Smad7-induced abnormalities in hair follicles and sebaceous glands. Conversely, when endogenous Smad7 was knocked down, keratinocytes exhibited increased beta-catenin protein and enhanced Wnt signaling. Our data reveal a mechanism for Smad7 in antagonizing Wnt/beta-catenin signaling, thereby shifting the skin differentiation program from forming hair follicles to sebaceous glands.

So a TGF-Beta antagonist decreases Wnt signalling. Wouldn't everything make much more sense if TGF-Beta signalling opposed wnt/beta-catenin pathway? We could kind of tie everything together nice and neatly then. Androgens -> ROS + dickkopf + tgf-B -> inhibit wnt pathway. A more or less common mechanism. Maybe too neat. Such is the way the world works. Interestingly the wnt effect of SMAD7 was noted as being independent of its role in inhibiting TGF-Beta.
hh

 

[harold]

Harold,

I'll see what I can find.

By the way, the poster you mentioned is the esteemed "Fred102" aka sinere-advisor. Fred is a long time hair researcher.

I was very impressed by his knowledge in that post and especially that he had all this sorted out way back then. I remember people talking about beta-catenin back in the days when I was first getting into all this but I never really got why they were so interested.
hh

 

[S Foote.]

If you go through all of them and research the function of each one a rather interesting picture develops. What you have is a plethora of molecules associated with an inflammatory response; be it endothelial or epithelial in origin. What you also have is a wide array of molecules associated with establishing a pro-apoptotic environment, as well as, a pro-fibrotic environment.

On the other hand, there are also a few molecules upregulated in there that are clearly pro-growth. It really does look as though the body is trying to upregulate growth, but it simply can't overcome all the negative growth signals.

Definitely a good post.

http://www.ncbi.nlm.nih.gov/entrez/quer ... s=16834456

S Foote.

.."increase in the number and size of microlymphatic structures in the lymphedematous cutaneous tissues"

"acute post-surgical lymphedema in the tails of female hairless, immunocompetent SKH-1 mice"

"In the mouse tails that had had their lymph vessels damaged, the authors were able to show that the tails were swollen compared with those of normal animals and of animals that hadhad sham (pretend) surgery. In the animals with lymphedema, many small lymph vessels were seen, as the lymph was unable to flow away normally"

"There was a notable increase in cellularity, with an increase in the number of observed fibroblasts and histiocytes, as well as a large infiltration of neutrophils Granulation tissue was observed closer to the center of the section, with bystander destruction of muscle tissue. In addition, there was hyperkeratosis and spongiosis and edema of the epidermis, with irregularity of the epidermal/dermal junction, elongation of the dermal papillae, and a 2- to 3-fold expansion of tissue between the bone and the epidermis. Lymphedema specimens were characterized by the presence of numerous dilated lymphatics in the dermis and subdermis, as seen in Figure 2B."


There are at least two genes that upregulated in a similar manner with regards to lymphedema and hair loss if you go through what has been posted here and the tables that they give in the study that demonstrate the upregulation and downregulation of specific genes. Unfortunately, those genes don't even make the top five for hair loss. Heme oxygenase is one and TGF-beta2 is the other. Both are expected to be upregulated in any inflammatory process, so one can not make a conclusion either way.

Another problem with this study is that a good researcher would realize that you can not compare acute disease to chronic disease. In the study you posted, they physically induced a lymphedematous reaction surgically in an acute manner. There was clear swelling, as well as, clear histological changes demonstrating what the researchers viewed throughout their experiments. male pattern baldness does not demonstrate the same histological characteristics. Hyperkeratosis can sometimes be visualized in male pattern baldness, but spongiosis and edema are rarely seen. An inflammatory infiltrate is also a rarity at the microscopic level. I have never seen evidence for dilated lymphatic vessels or lymphatic vessel hyperplasia. Lastly, bystander muscle destruction is unheard of in androgenic alopecia.

The majority of the inflammation in male pattern baldness is confined to the infundibulum. It is not trans-epithelial, nor is it muscle destroying.


I can see how the two process would seem both similar and confusing to you.

They are not confusing to me, or anyone else who can see the obvious connections. As Michael pointed out, it is a pity there was no hair present to test as in the original study in this thread.

And we do have a clear example for ineficient lymphatics in the scalp of "HUMANS", and follicle miniaturisation. This has been studied histologicaly in lipedemous alopecia.

http://alopecia.researchtoday.net/archive/1/2/66.htm

Quote.

". CONCLUSIONS: Our findings suggest a lessened role of racial factors, but confirms the sex implications in these related conditions, and stress the potential significance of lymphangiectatic vessels in the development of alopecia in these patients."

You can theorise all you want about what particular molecules etc play in male pattern baldness, but this was a "hard" in-vivo human study that shows your assumptions above to be wrong Doctor. Of course any growth restriction in follicles for "whatever" reason, is "THEN" going to show growth related gene expression changes. But this tells us nothing about the actual "cause" of the changes related to DHT. But i get sick of trying to point out the obvious!

Michael.

This is a study you may want to point out to Armando? As i said, i don't have time anymore to get involved in arguments on these boards.

http://www.blackwell-synergy.com/doi/ab ... 05.06953.x

S Foote.