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TGF-BETA and inflammation


#1

I found this on another site, it confirmed what I have been saying all along, that androgens are not the only reason why we are losing hair.

WHAT’S NEW IN ANDROGENETIC ALOPECIA

A. Tosti, BM Piraccini, S. Mantovani Department of Dermatology University of Bologna, Italy.

Androgenetic alopecia is the most common type of hair loss in both men and women. Accumulating evidence indicates that androgens are not the only factor involved in the pathogenesis of this condition but that other elements may be important as well. Recent work indicates that androgenetic alopecia in men is a different pathophysiologic event as compared to androgenetic alopecia
in women. In women, miniaturization is not the main event. Hair loss is mostly correlated with reduced hair density and the “empty follicle phenomenon” can be very important in determining this
feature. The finding that miniaturization may not be gradual but rather occurs rapidly is also new.

The role of inflammation and seborrheic dermatitis in the etiology of hair loss has been debated for years but today we have consistent data to conclude that the inflammation that often accompanies
androgenetic alopecia is an important aggravating factor. Inflammation can accelerate the progression of
hair loss by promoting telogen effluvium and may also induce perifollicular fibrosis and scarring.

Microinflammation may therefore be a significant factor in determining long-term prognosis as well as response to treatment.

We have recently found a significative association between superficial perifollicular lymphocytic infiltration and the presence of peripilar signs at the scalp dermoscopy.

Although it is easy for any dermatologist to recognize and diagnose androgenetic alopecia just by looking at the patient, we still lack of a simple and reliable method to evaluate severity of androgenetic
alopecia. The lack of such methods compromises our ability to diagnose early disease. Still, patients frequently require hair analysis and as dermatologists we should be able to perform the test using good and reliable methods.

Distinguishing between normal and abnormal hair loss can even be more difficult in middle-aged individuals where androgenetic alopecia and senescent thinning of the hair may be associated or even
overlap.

ANDROGENS ACTION IN HUMAN HAIR FOLLICLES

S. Itami. Osaka University School of Medicine, Osaka, Japan.

Hair growth cycle is coordinated and complex processes that are dependent on the interactions of epithelial and dermal components. Although the precise mechanism of hair growth regulation by the hormone is yet to be established, beard, axillary and frontal scalp dermal papilla cells (DPCs) possess the characteristics of androgen target cells. Beard, and frontal scalp DPCs expressed androgen receptor (AR) and type II 5alpha-reductase mRNA. In order to know the mode of androgen action in human hair follicles, we developed an in vitro coculture system using human dermal papilla cells (DPCs) and outer root sheath cells. Androgen significantly stimulated the proliferation of outer root sheath cells cocultured with beard or axillary DPCs, suggesting that these DPCs produce androgen-dependent
diffusible growth factors. Insulin-like growth factor-I (IGF-I) was
identified as one of the androgen dependent paracrine growth factors in beard DPC. Although androgen stimulates the beard growth, it
paradoxically suppresses the growth of frontal scalp hair of androgenetic alopecia in vivo. We attempted establishing an in vitro coculture system using DPCs from androgenetic alopecia (AGA) and
keratinocytes (KCs) to explore the pathomechanism of AGA. Since the
expressions of mRNA of AR decreased during subcultivation of DPCs in vitro, we transiently transfected the AR expression vector into the

DPCs and cocultured them with KCs. In this modified coculture, androgen significantly suppressed the growth of KCs, indicating that overexpression of AR can restore the responsiveness of the DPCs to
androgen in vivo. We found that androgen up-regulated the expression of TGF-beta mRNA in the cocultured DPCs. Androgen stimulated the secretion of both total and active TGF-_1 in the conditioned medium,
suggesting that activation process of TGF-beta is also involved in the androgen-induced suppression of epithelial cell growth. We proposed that this modified coculture system is a powerful in vitro model to elucidate the pathomechanism of androgenetic alopecia.

words from myself:

the interesting quotes from the study i have posted below (READ THE WHOLE ABSTRACT PLEASE):

“Among these factors, epidermal growth factor (EGF), as
well as pro-inflammatory cytokines, play a pivotal role, as evidenced by their direct inhibitory effects on hair growth both in vitro and in vivo.”

“Cytokine-and EGF-induced upregulation of MMP-9 in the lower epithelial compartment of the human hair bulb is a major mechanism through which hair follicle involution, observed in alopecia, may occur”

Identification of clustered cells in human hair follicle responsible
for MMP-9 gelatinolytic activity: consequences for the regulation of
hair growth.

Jarrousse F, Boisnic S, Branchet MC, Beranger JY, Godeau G, Breton
L, Bernard BA, Mahe YF.

Hair Biology Research Group and Cutaneous Physiology Department, L’
OREAL, Clichy Cedex, GREDECO, Paris, France.

BACKGROUND: The control of human hair follicle growth and
differentiation is dependent upon several well-identified factors,
including androgens, cytokines, and growth factors. In humans, alopecia androgenetica is a common aging process thought to be regulated through complex genetic imbalances, which also involve several of these crucial identified factors (and probably others not yet characterized), alone or in combination. Among these factors, epidermal growth factor (EGF), as well as pro-inflammatory cytokines, play a pivotal role, as evidenced by their direct inhibitory effects on hair growth both in vitro and in vivo. Following such treatments, the in vitro growth of hair follicles
was rapidly arrested and deleterious modifications of hair morphology
were also observed. AIM: Because these cytokines act, at least partly, through the induction of matrix metalloproteinases (MMP), and because tissue remodeling occurs during the hair cycle, we attempted to identify and localize MMP in the human pilosebaceous unit. METHOD: We used zymography to observe human hair follicles in culture in vitro.

RESULTS:
We observed that human hair follicles in culture in vitro mainly and
almost exclusively produce MMP-2 and MMP-9 gelatinolytic activities.
Furthermore, after stimulation with EGF, tumor necrosis factor-alpha
(TNF-alpha), or interleukin-1alpha (IL-1alpha), MMP-9 production was
strongly increased. Using immunohistochemistry, we then precisely
localized MMP-9 in the lower part of the inner root sheath (Henle’s
layer) of control human anagen hair follicles. CONCLUSIONS: Cytokine-
and EGF-induced upregulation of MMP-9 in the lower epithelial
compartment of the human hair bulb is a major mechanism through which
hair follicle involution, observed in alopecia, may occur.

also see:

Improvement in the inflammatory aspect of androgenetic alopecia. A pilot study with an antimicrobial lotion. Journal of Derm. Treat. (1996) 7, 153-157.

Androgenetic alopecia and microinflammation.
Int J Dermatol. 2000 Aug;39(8):576-84. Review.

Characterization of inflammatory infiltrates in male pattern alopecia: implications for pathogenesis.

Br J Dermatol. 1992 Sep;127(3):239-46.

Cutaneous immunopathology of androgenetic alopecia. J Am Osteopath Assoc. 1991 Aug;91(8) 65-71.

Also, Whiting showed the presence of inflammation decreases response to Minoxidil treatments. So, it’s more than just a coincidence, it actually inhibits hair growth.

Secondly, inflammatory cytokines (TNF, IL-1) secreted around the hair follicle are known, potent hair growth inhibitors.



tgf-beta section:

Androgen-inducible TGF-beta1 from balding dermal papilla cells inhibits epithelial cell growth: a clue to understand paradoxical effects of androgen on human hair growth.
Inui S, Fukuzato Y, Nakajima T, Yoshikawa K, Itami S.
Department of Dermatology, Course of Molecular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.

We attempted establishing an in vitro coculture system by using human
dermal papilla cells (DPCs) from androgenetic alopecia (AGA) and
keratinocytes (KCs) to explore the role of androgens in hair growth
regulation. Androgen showed no significant effect on the growth of KCs when they were cocultured with DPCs from AGA. Because the expressions of mRNA of androgen receptor (AR) decreased during subcultivation of DPCs in vitro, we transiently transfected the AR expression vector into the DPCs and cocultured them with KCs. In this modified coculture, androgen significantly suppressed the growth of KCs by approximately 50%, indicating that overexpression of AR can restore the responsiveness of the DPCs to androgen in vivo. We found that androgen stimulated the expression of TGF-beta1 mRNA in the cocultured DPCs. ELISA assays demonstrated that androgen treatment increased the secretion of both total and active TGF-beta1 in the conditioned medium. Moreover, the neutralizing anti-TGF-beta1 antibody reversed the androgen-elicited growth inhibition of KCs in a dose-dependent manner. These findings suggest that androgen-inducible TGF-beta1 derived from DPCs of AGA is involved in epithelial cell growth suppression in our coculture system, providing the clue to understand the paradoxical effects of androgens
for human hair growth.

PMID: 12397096

Androgen receptor-mediated inhibition of cutaneous wound healing.
Ashcroft GS, Mills SJ. Cells, Immunology and Development, School of Biological Sciences, University of Manchester, Manchester, United Kingdom.

Impaired wound healing states in the elderly lead to substantial
morbidity, mortality, and a cost to the US Health Services of over $9
billion per annum. In addition to intrinsic aging per se causing delayed healing, studies have suggested marked sex-differences in wound repair.

We report that castration of male mice results in a striking
acceleration of local cutaneous wound healing, and is associated with a reduced inflammatory response and increased hair growth. Using a hairless mouse model, we have demonstrated that testosterone reduction stimulates the healing response not through hair follicle
epithelial/mesenchymal cell proliferation, but directly via effects on wound cell populations. We suggest that endogenous testosterone inhibits the cutaneous wound healing response in males and is associated with an enhanced inflammatory response. The mechanisms underlying the observed effects involve a direct upregulation of proinflammatory cytokine expression by macrophages in response to testosterone. Blockade of androgen action systemically, via receptor antagonism, accelerates healing significantly, suggesting a specific target for future therapeutic intervention in impaired wound healing states in elderly males.
PMID: 12208862

Involvement of Transforming Growth Factor-beta2 in Catagen Induction During the Human Hair Cycle.

J Invest Dermatol 2002 Jun;118(6) 93-7.

The involvement of transforming growth factor-beta isoforms in the induction of the regressing phase (catagen) of human hair follicles were examined in vivo. In the growing phase (anagen), transforming growth factor-beta1 was detected at the hair cuticle and connective tissue sheath. Transforming growth factor-beta2 was restricted to the outermost cell layer of the outer root sheath. Transforming growth factor-beta3 was observed in the precortical hair matrix of anagen hair follicles. During the anagen-catagen transition phase, strong transforming growth factor-beta2 immunoreactivity appeared in the lower bulb matrix cells adjacent to the dermal papilla. In addition, transforming growth factor-beta2 and transforming growth
factor-beta type II receptor were colocalized in the regressing epithelial strands, where terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling-positive apoptotic cells were also found.

Transforming growth factor-beta1 and transforming growth factor-beta3 were mostly negative in the strand. Using an organ culture system, we investigated whether transforming growth factor-beta2 and its antagonists affected the transition process. Elongation of hair was significantly suppressed by transforming growth factor-beta2. Next, a neutralizing antibody and fetuin, a potent transforming growth factor-beta antagonist was tested. In the presence of the antibody as well as fetuin, hair follicles were markedly elongated in a concentration-dependent manner. These results strongly suggest that transforming growth factor-beta2 plays an essential part in the induction of the catagen phase of the human hair cycle.

Dose-dependent inhibition of hepatic fibrosis in mice by a TGF-beta soluble receptor: implications for antifibrotic therapy.

Hepatology 2002 May;35(5):1022-30.

Transforming growth factor (TGF) beta isoforms (in particular, TGF-beta1) play a central role in the fibrogenic response to injury in many organs, including the liver. Although TGF-beta is clearly important in fibrogenesis, a number of issues related to therapeutic antagonism have emerged. For example, the long-term effect of TGF-beta antagonism is unknown; furthermore, controversy exists as to appropriate levels of TGF-beta inhibition. Therefore, we aimed to examine TGF-beta in models of chronic liver injury and to determine whether an in vivo dose-response relationship exists for inhibition of TGF-beta. Liver injury was induced in BALB/c mice by administering carbon tetrachloride for 4 or 8 weeks. TGF-beta binding was inhibited with a soluble TGF-beta type II receptor (STR) construct, administered intraperitoneally over a dose range of 4.0, 1.0, 0.4, or 0.1 mg/kg twice weekly during fibrogenesis. Fibrogenesis was assessed by measurement of type I collagen messenger RNA (mRNA) expression and by quantitative morphometric analysis. In the 4-week study, STR at concentrations of 4.0, 1.0, and 0.1 mg/kg reduced type I collagen mRNA expression by 31%, 49%, and 60% compared with immunoglobulin (Ig) G controls, respectively. In the 8-week study, lower concentrations of STR (0.1 mg/kg) also had the greatest effect on type I collagen mRNA expression.

Quantitative morphometrics similarly showed that lower concentrations of STR were the most antifibrogenic. In conclusion, the results confirm the antifibrotic effect of inhibiting TGF-beta in chronic hepatic wounding and, moreover, show that its in vivo effect in the mouse is dose dependent. Such findings have major translational implications for therapeutic strategies aimed at TGF-beta.

PMID: 11981752

PMID: 12060393

More proof that there is more to mpb than androgens:
http://www.lion.co.jp/en/press/pdf/pre24-00.pdf


#2

» I found this on another site, it confirmed what I have been saying all
» along, that androgens are not the only reason why we are losing hair.

But those other things are still DOWNSTREAM EFFECTS of androgens.

.