Download Steht die Psyche unter Druck, leiden die Haare – eine

Steht die Psyche unter Druck, leiden die Haare – eine Erfahrung, die bereits viele gemacht haben. Jetzt
gibt es auch Studien, die diese These wissenschaftlich untermauern. Stresshormone entfalten beim
Abbau im Körper ähnliche Wirkungen wie Androgene. Sie schaden den Haarwurzeln. Ralf Paus: „Unsere
Versuche mit Mäusen zeigen, dass sich chronischer Stress negativ auf das Haarwachstum auswirkt. Die
Wurzeln entzünden sich, der programmierte Zelltod tritt häufiger ein, die Haare beenden ihre
Wachstumsphase deutlich früher.“ Auch wenn es noch unklar ist, ob diese Beobachtungen auch für
den Menschen gelten, dürfte der negative Einfluss von Stress auf den Haarwuchs deutlich größer sein,
als man lange angenommen hat.
Die viel diskutierte – aber nie belegte – „Vermännlichung“ der Frau als Ursache für Haarausfall liegt
vermutlich hier begründet. Frauen, die durch Karriere, Familie und Haushalt mehrfach belastet sind,
werden nicht männlicher. Sie haben einfach mehr Stress und lassen deshalb Haare.
Targets für Mittel gegen Haarausfall
Hautklinik am Universitätsklinikum Hamburg-Eppendorf
Wirksame Mittel gegen Haarausfall müssen möglichst gezielt an einer Reihe definierter
Pathomechanismen ansetzen, die sich hinter Alopezie/Effluvium verbergen können:
1. Haarzyklusstörungen
2. Termin-zu-Vellus- und Vellus-zu-Terminal-Haarkonversionsstörungen
3. irreversible) Störungen des follikulären Regenerationspotentials
4. Störungen der physiologischen "programmierten Organdeletion" (POD) von Haarfollikeln
5. Störungen des antimikrobiellen Abwehrsystems des Haarfollikels
6. Kollaps des Haarfollikel-Immunsystems
7. Störungen der Haarschaftproduktion
Vordringlich ist die Entwicklung von Haarzyklus-Modulatoren, da die in der Praxis am häufigsten
beobachteten Haarwuchstörungen zumindest zu einem wesentlichen Teil Haarzyklusstörungen
repräsentieren. Dabei gilt der einfache Merksatz: Ist die Anagenphase zu kurz und die Katagenphase
setzt zu früh ein, kommt es zu Alopezie/Effluvium. Ist umgekehrt die Anagenphase zu lang und die
Katagenphase setzt zu spät ein, treten Hirsutismus/Hypertrichose auf. Dermatopharmazeutisch ist
insbesondere die Entwicklung solcher Medikamente von besonderer klinischer Bedeutung, die
effizient und nebenwirkungsarm die Katagenphase hemmen oder induzieren können. Im Vordergrund
steht dabei die Manipulation der Apoptose von Haarfollikelkeratinozyten, da die Katagenphase des
Haarzyklus ein Apoptose-getriebener Organinvolutionsprozeß ist. Studien aus dem Maussystem, die
Glukokortikoide und Immunophilinliganden als außerordentlich potente Katagenmanipulatoren
identifiziert haben, sowie jüngere Arbeiten, die wichtige Unterschiede in der Apoptoseregulation von
epidermalen und follikulären Keratinozyten und die Rolle bestimmter Wachstumsfaktoren in der
Katagenregulation herausgearbeitet haben, liefern wichtige Anhaltspunkte für vielversprechende
Zielgene und Signaltransduktionswege.
Weit rudimentärer sind dagegen unsere bisherigen Kenntnisse zu den anderen Pathomechanismen.
Diese werden am Beispiel relevanter Haarwuchsstörungen kurz erläutert, um mögliche
dermatopharmazeutische Behandlungsansätze zu skizzieren. Betont wird die klinische Bedeutung der
Entwicklung von Stammzell-protektiven Pharmaka (insbesondere bei Chemotherapie- und
Radiotherapie-induzierter Alopezie sowie bei vernarbenden Alopezien) und von Pharmaka, die ein
zusammengebrochenens follikuläres Immunprivileg wieder restituieren können. Aus diesen
Erwägungen lassen sich klare Strategien für die Entwicklung effizienterer und innovativer
"Trichopharmaka" ableiten, die idealerweise topisch applizierbar sein und bevorzugt oder gar exklusiv
auf den Haarfollikel wirken sollten (z.B. durch Einsatz von "follicle targeting"-Liposomen).
Burden of hair loss: stress and the underestimated psychosocial impact of telogen effluvium and androgenetic alopecia.
Hadshiew IM, Foitzik K, Arck PC, Paus R
J Invest Dermatol 2004 Sep;123(3):455-7.
Department of Dermatology, University Hospital Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany. FAU - Hadshiew, Ina M
PMID: 15304082 [PubMed - indexed for MEDLINE]
Hair loss, as it occurs with telogen effluvium and androgenetic alopecia, provokes anxieties and distress more profound than its objective severity would appear to justify. This reflects the profound symbolic and psychosocial
importance of hair. Stress has long been implicated as one of the causal factors involved in hair loss. Recently, in vivo studies in mice have substantiated the long-held popular belief that stress can exert profound hair growthinhibitory catagen-inducing and hair-damaging pro-inflammatory effects. Insights into the negative impact of stress on hair growth and the integration of stress-coping strategies into the management of hair loss disorders as well
as the development of new pharmacotherapeutic strategies might lead to enhanced therapeutic modalities with the alleviation of clinical symptoms as well as the concomitant psychological implications.
Neurogenic inflammation in stress-induced termination of murine hair growth is promoted by nerve growth factor.
Peters EM, Handjiski B, Kuhlmei A, Hagen E, Bielas H, Braun A, Klapp BF, Paus R, Arck PC
Am J Pathol 2004 Jul;165(1):259-71.
Center for Biomedical Research, Charite, University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. FAU - Peters, Eva Milena J
PMID: 15215181 [PubMed - indexed for MEDLINE]
Recently, we have revealed the existence of a "brain-hair follicle axis" in murine skin and have identified the neuropeptide substance P (SP) as a key mediator of stress-induced hair growth inhibition in vivo. Published evidence
suggests that increased numbers of SP-immunoreactive sensory fibers, as seen in the dermis of stressed mice in anagen-catagen transition, are a result of transient high levels of nerve growth factor (NGF). Thus, we now aimed
at dissecting the role of NGF in stress-triggered hair growth termination in our murine model. By real time PCR and immunohistochemistry, stress-exposed mice showed an up-regulation of NGF and its low-affinity receptor
p75NTR; the NGF high-affinity receptor TrkA was moderately down-regulated. On neutralization of NGF, premature onset of catagen, apoptosis, and increased number/activation of perifollicular mast cells and antigen-presenting
cells, which reflects the skin response to stress, was significantly abrogated. Stress or subcutaneous injection of recombinant NGF (to mimic stress) resulted in an increased percentage of SP(+) neurons in dorsal root ganglia, as
measured by retrograde tracing. Taken together, these data suggest that NGF is a central element in the perifollicular neurogenic inflammation that develops during the murine skin response to stress and antagonizing NGF may
be a promising therapeutic approach to counter the negative effect of stress on hair growth.
Neurotrophin-3 regulates mast cell functions in neonatal mouse skin.
Metz M, Botchkarev VA, Botchkareva NV, Welker P, Tobin DJ, Knop J, Maurer M, Paus R
Exp Dermatol 2004 May;13(5):273-81.
Department of Dermatology, University Hospital Mainz, Mainz, Germany. FAU - Metz, Martin
PMID: 15140017 [PubMed - indexed for MEDLINE]
Nerve growth factor (NGF) has long been recognized as an important mast cell (MC) growth factor. To explore whether other neurotrophins (NTs) of the NGF family, which are widely expressed in mouse skin, affect the numbers
and/or functions of MCs we examined the effects of NT-3 on neonatal skin MCs. We demonstrate that TrkC, the high affinity NT-3 receptor, is expressed by virtually all neonatal skin MCs in C57BL/6 mice, which indicates that
MCs can respond to NT-3. Skin of neonatal and early postnatal NT-3-overexpressing mice (promoter: K14) displayed significantly and up to twofold increased numbers of MCs during the first 20 days after birth, as compared to
wild-type mice. To check whether this increase in MC numbers in NT-3 transgenic mice reflects a higher rate of proliferation, we performed immunohistochemistry, which revealed that only 1-2% of all skin MCs both in NT-3overexpressing and in wild-type controls showed Ki-67-positive nuclei, suggesting that the observed differences in the number of MCs do not reflect a higher rate of MC proliferation. Additionally, we show that the effect of NT-3
on the number of MCs is most likely to be stem cell factor (SCF)-independent, because NT-3 significantly downregulates secretion of SCF-protein in cultured dermal fibroblasts, as assessed by enzyme-linked immunosorbent
assay. Numbers of skin MCs in neonatal TrkC-deficient mice were found to be modestly reduced, as compared to wild-type mice, indicating that NT-3 can modulate the number of MCs directly via TrkC, although TrkC does not
seem to be essential for the number of basal MCs. To further analyze the effects of NT-3 on MCs, we stimulated skin organ culture of early postnatal C57BL/6 mouse skin with 5-50 ng/ml NT-3, which induced a significant
increase in MC degranulation, as visualized by Giemsa staining. However, stimulation of isolated neonatal dermal skin MCs with NT-3 in vitro failed to result in MC activation, as measured by serotonin release. Our data suggest
a role for NT-3 in the maturation of MCs, such as a TrkC-mediated stimulation of the differentiation of pre-existing, less mature MCs and/or by enhancing the migration of circulating MC precursors into the skin.
Stichworte:
Collapse and restoration of MHC class-I-dependent immune privilege: exploiting the human hair follicle as a model.
Ito T, Ito N, Bettermann A, Tokura Y, Takigawa M, Paus R
Am J Pathol 2004 Feb;164(2):623-34.
Department of Dermatology, University Hospital Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany. FAU - Ito, Taisuke
PMID: 14742267 [PubMed - indexed for MEDLINE]
The collapse of major histocompatibility complex (MHC) class-I-dependent immune privilege can lead to autoimmune disease or fetal rejection. Pragmatic and instructive models are needed to clarify the as yet obscure controls of
MHC class I down-regulation in situ, to dissect the principles of immune privilege generation, maintenance, and collapse as well as to develop more effective strategies for immune privilege restoration. Here, we propose that
human scalp hair follicles, which are abundantly available and easily studied, are ideally suited for this purpose: interferon-gamma induces ectopic MHC class I expression in the constitutively MHC class-I-negative hair matrix
epithelium of organ-cultured anagen hair bulbs, likely via interferon regulatory factor-1, along with up-regulation of the MHC class I pathway molecules beta(2)microglobulin and transporter associated with antigen processing
(TAP-2). In the first report to identify natural immunomodulators capable of down-regulating MHC class I expression in situ in a normal, neuroectoderm-derived human tissue, we show that ectopic MHC class I expression in
human anagen hair bulbs can be normalized by treatment with alpha-MSH, IGF-1, or TGF-beta1, all of which are locally generated, as well as by FK506. These agents are promising candidates for immune privilege restoration
and for suppressing MHC class I expression where this is clinically desired (eg, in alopecia areata, multiple sclerosis, autoimmune uveitis, mumps orchitis, and fetal or allograft rejection).
Epithelial growth control by neurotrophins: leads and lessons from the hair follicle.
Botchkarev VA, Botchkareva NV, Peters EM, Paus R
Prog Brain Res 2004;146:493-513.
Department of Dermatology, Boston University School of Medicine, Boston, MA, USA. FAU - Botchkarev, Vladimir A
PMID: 14699982 [PubMed - indexed for MEDLINE]
Neurotrophins (NTs) exert many growth-regulatory functions beyond the nervous system. For example, murine hair follicles (HF) show developmentally and spatio-temporally stringently controlled expression of NTs, including
nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4, and their cognate receptors, tyrosine kinase A-C (TrkA-C) and p75 neurotrophin receptor (p75NTR). Follicular NT and NT
receptor expression exhibit significant, hair cycle-dependent fluctuations on the gene and protein level, which are mirrored by changes in nerve fiber density and neurotransmitter/neuropeptide content in the perifollicular neural
networks. NT-3/TrkC and NGF/TrkA signaling stimulate HF development, while NT-3, NT-4 and BDNF inhibit the growth (anagen) of mature HF by the induction of apoptosis-driven HF regression (catagen). p75NTR stimulation
inhibits HF development and stimulates catagen. Since the HF is thus both a prominent target and key peripheral source of NT, dissecting the role of NTs in the control of HF morphogenesis and cyclic remodeling provides a
uniquely accessible, and easily manipulated, clinically relevant experimental model, which has many lessons to teach. Given that our most recent data also implicate NTs in human hair growth control, selective NT receptor
agonists and antagonists may become innovative therapeutic tools for the management of hair growth disorders (alopecia, effluvium, hirsutism). Since, however, the same NT receptor agonists that inhibit hair growth (e.g., BDNF,
NT-4) can actually stimulate epidermal keratinocyte proliferation, NT may exert differential effects on defined keratinocyte subpopulations. The studies reviewed here provide new clues to understanding the complex roles of NT in
epithelial tissue biology and remodeling in vivo, and invite new applications for synthetic NT receptor ligands for the treatment of epithelial growth disorders, exploiting the HF as a lead model.
Molecular biology of hair morphogenesis: development and cycling.
Botchkarev VA, Paus R
J Exp Zoolog Part B Mol Dev Evol 2003 Aug 15;298(1):164-80.
Department of Dermatology, Boston University School of Medicine, Boston, MA, USA. [email protected] FAU - Botchkarev, Vladimir A
PMID: 12949776 [PubMed - indexed for MEDLINE]
In mammals, hair follicles produce hairs that fulfill a number of functions including thermoregulation, collecting sensory information, protection against environmental trauma, social communication, and mimicry. Hair follicles
develop as a result of epithelial-mesenchymal interactions between epidermal keratinocytes committed to hair-specific differentiation and cluster of dermal fibroblasts that form follicular papilla. During postnatal life, hair follicles
show patterns of cyclic activity with periods of active growth and hair production (anagen), apoptosis-driven involution (catagen), and relative resting (telogen). During last decade, substantial progress has been achieved in
delineating molecular mechanisms that control hair follicle development and cyclic activity. In this review, we summarize the data demonstrating that regulation of hair follicle development in the embryo and control of hair follicle
growth during postnatal life are highly conserved and both require involvement of similar molecular mechanisms. Since many of the molecules that control hair follicle development and cycling are also involved in regulating
morphogenesis and postnatal biology of other ectodermal derivatives, such as teeth, feathers, and mammary glands, basic principles and molecular mechanisms that govern hair follicle development and growth may also be
applicable for other developmental systems. CI - Copyright 2003 Wiley-Liss, Inc.
Plasticity and cytokinetic dynamics of the hair follicle mesenchyme during the hair growth cycle: implications for growth control and hair follicle transformations.
Tobin DJ, Gunin A, Magerl M, Paus R
J Investig Dermatol Symp Proc 2003 Jun;8(1):80-6.
Department of Biomedical Sciences, School of Life Sciences, University of Bradford, Bradford, West Yorkshire, UK. [email protected] FAU - Tobin, Desmond J
PMID: 12895000 [PubMed - indexed for MEDLINE]
Hair fiber production is the macroscopic end-point of a highly complex set of interactions between the hair follicle's epithelial and mesenchymal components. The nature of this relationship is largely set during hair follicle
morphogenesis, but is dramatically revisited in the adult during the unique tissue remodeling events required for hair follicle cycling. Whereas significant attention has focused on the fate of the hair follicle epithelium during these
events, associated changes in hair follicle fibroblast subpopulations remain unclear. Here, we present a speculative review that represents a critical and innovative synthesis of the current literature and summarizes a recently
submitted original study by the authors, on the nature of hair cycle-dependent fibroblast dynamics and on how perturbations thereof may lead to several clinical manifestations of altered human hair growth.
Stress inhibits hair growth in mice by induction of premature catagen development and deleterious perifollicular inflammatory events via neuropeptide substance P-dependent pathways.
Arck PC, Handjiski B, Peters EM, Peter AS, Hagen E, Fischer A, Klapp BF, Paus R
Am J Pathol 2003 Mar;162(3):803-14.
Department of Internal Medicine, Charite School of Medicine, Humboldt University, Berlin, Germany. [email protected] FAU - Arck, Petra Clara
PMID: 12598315 [PubMed - indexed for MEDLINE]
It has been much disputed whether or not stress can cause hair loss (telogen effluvium) in a clinically relevant manner. Despite the paramount psychosocial importance of hair in human society, this central, yet enigmatic and
controversial problem of clinically applied stress research has not been systematically studied in appropriate animal models. We now show that psychoemotional stress indeed alters actual hair follicle (HF) cycling in vivo, ie,
prematurely terminates the normal duration of active hair growth (anagen) in mice. Further, inflammatory events deleterious to the HF are present in the HF environment of stressed mice (perifollicular macrophage cluster,
excessive mast cell activation). This provides the first solid pathophysiological mechanism for how stress may actually cause telogen effluvium, ie, by hair cycle manipulation and neuroimmunological events that combine to
terminate anagen. Furthermore, we show that most of these hair growth-inhibitory effects of stress can be reproduced by the proteotypic stress-related neuropeptide substance P in nonstressed mice, and can be counteracted
effectively by co-administration of a specific substance P receptor antagonist in stressed mice. This offers the first convincing rationale how stress-induced hair loss in men may be pharmacologically managed effectively.
Control of pelage hair follicle development and cycling by complex interactions between follistatin and activin.
Nakamura M, Matzuk MM, Gerstmayer B, Bosio A, Lauster R, Miyachi Y, Werner S, Paus R
FASEB J 2003 Mar;17(3):497-9. Epub 2003 Jan 2.
Department of Dermatology, University Hospital Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany. FAU - Nakamura, Motonobu
PMID: 12514121 [PubMed - indexed for MEDLINE]
Members of the transforming growth factor beta/bone morphogenetic protein (TGF-beta/BMP) family are involved in the control of hair follicle (HF) morphogenesis and cycling. The activities of several members of this family
activins and BMP-2, -4, -7, and -11) are controlled by antagonists such as follistatin. Because follistatin-deficient mice show abnormalities in vibrissae development, we explored the role of follistatin and activin in pelage HF
development and cycling. We show here that during HF development follistatin mRNA was prominently expressed by hair matrix and outer root sheath keratinocytes as well as by interfollicular epidermal cells, whereas activin
betaA mRNA was mainly expressed in dermal papilla cells. Compared with age-matched wild-type controls, both follistatin knockout mice and activin betaA transgenic mice showed a significant retardation of HF morphogenesis.
Treatment of wild-type embryonic skin explants with follistatin protein stimulated HF development. This effect was inhibited by addition of recombinant activin A protein. Activin betaA transgenic mice demonstrated retardation of
catagen entry, down-regulation of BMP-2, and up-regulation of expression of its antagonist matrix GLA protein. These observations suggest that follistatin and activin interaction plays an important role in both HF development
and cycling, possibly in part by regulating expression of BMP-2 and its antagonist.
The lysosomal protease cathepsin L is an important regulator of keratinocyte and melanocyte differentiation during hair follicle morphogenesis and cycling.
Tobin DJ, Foitzik K, Reinheckel T, Mecklenburg L, Botchkarev VA, Peters C, Paus R
Am J Pathol 2002 May;160(5):1807-21.
Department of Biomedical Sciences, University of Bradford, Bradford, England. FAU - Tobin, Desmond J
PMID: 12000732 [PubMed - indexed for MEDLINE]
We have previously shown that the ubiquitously expressed lysosomal cysteine protease, cathepsin L (CTSL), is essential for skin and hair follicle homeostasis. Here we examine the effect of CTSL deficiency on hair follicle
development and cycling in ctsl(-/-) mice by light and electron microscopy, Ki67/terminal dUTP nick-end labeling, and trichohyalin immunofluorescence. Hair follicle morphogenesis in ctsl(-/-) mice was associated with several
abnormalities. Defective terminal differentiation of keratinocytes occurred during the formation of the hair canal, resulting in disruption of hair shaft outgrowth. Both proliferation and apoptosis levels in keratinocytes and
melanocytes were higher in ctsl(-/-) than in ctsl(+/+) hair follicles. The development of the hair follicle pigmentary unit was disrupted by vacuolation of differentiating melanocytes. Hair cycling was also abnormal in ctsl(-/-) mice.
Final stages of hair follicle morphogenesis and the induction of hair follicle cycling were retarded. Thereafter, these follicles exhibited a truncated resting phase (telogen) and a premature entry into the first growth phase. Further
abnormalities of telogen development included the defective anchoring of club hairs in the skin, which resulted in their abnormal shedding. Melanocyte vacuolation was again apparent during the hair cycle-associated
reconstruction of the hair pigmentary unit. A hallmark of these ctsl(-/-) mice was the severe disruption in the exiting of hair shafts to the skin surface. This was mostly because of a failure of the inner root sheath (keratinocyte layer
next to the hair shaft) to fully desquamate. These changes resulted in a massive dilation of the hair canal and the abnormal routing of sebaceous gland products to the skin surface. In summary, this study suggests novel roles for
cathepsin proteases in skin, hair, and pigment biology. Principal target tissues that may contain protein substrate(s) for this cysteine protease include the developing hair cone, inner root sheath, anchoring apparatus of the
telogen club, and organelles of lysosomal origin (eg, melanosomes).
Contrasting expression patterns of CCAAT/enhancer-binding protein transcription factors in the hair follicle and at different stages of the hair growth cycle.
Bull JJ, Muller-Rover S, Chronnell CM, Paus R, Philpott MP, McKay IA
J Invest Dermatol 2002 Jan;118(1):17-24.
Centre for Cutaneous Research, St Bartholomew's and the Royal London School of Medicine and Dentistry, London, UK. FAU - Bull, Jonathan J
PMID: 11851871 [PubMed - indexed for MEDLINE]
Hair follicles undergo repeated cycles of growth and regression, throughout the entire life of the organism. These dynamic changes require closely co-ordinated regulation of gene expression. The CCAAT/enhancer-binding
proteins are a family of basic region/leucine zipper transcription factors that regulate gene transcription in various tissues. They have been implicated in epidermal differentiation and may therefore play an important role in the hair
follicle. We have investigated the localization of four members of this family--CCAAT/enhancer-binding protein-alpha, -beta, and -delta, and Gadd153--in both human and murine hair follicles by immunohistochemistry.
Furthermore, we examined CCAAT/enhancer-binding protein-alpha, -beta, and -delta immunoreactivity at different stages of the depilation-induced murine hair growth cycle. Distinct immunoreactivity patterns for
CCAAT/enhancer-binding protein-alpha, -beta, and -delta, and Gadd153 were observed in the outer root sheath, sebaceous gland, dermal papilla, and connective tissue sheath of human anagen hair follicles. In murine follicles,
CCAAT/enhancer-binding protein-alpha was expressed in the outer root sheath, sebaceous gland, and dermal papilla, whereas CCAAT/enhancer-binding protein-beta expression was confined to the matrix, sebaceous gland,
and inner and outer root sheaths. Both CCAAT/enhancer-binding protein-alpha and -beta were upregulated during anagen, then downregulated in catagen follicles. In contrast, CCAAT/enhancer-binding protein-delta showed no
hair cycle-dependent variation in immunoreactivity. These data suggests that the expression of CCAAT/enhancer-binding protein-alpha and -beta may, in turn, play a part in regulating hair cycle-dependent gene expression.
Moreover, as CCAAT/enhancer-binding protein-alpha, -beta, and -delta are crucial in the regulation of adipocyte differentiation and lipid metabolism, their expression in sebocytes suggests they may also play a similar role in
differentiation and lipid metabolism of the sebaceous gland.
Indications for a 'brain-hair follicle axis (BHA)': inhibition of keratinocyte proliferation and up-regulation of keratinocyte apoptosis in telogen hair follicles by stress and substance P.
Arck PC, Handjiski B, Hagen E, Joachim R, Klapp BF, Paus R
FASEB J 2001 Nov;15(13):2536-8. Epub 2001 Sep 17.
Department of Internal Medicine, Charite, Humboldt University, Berlin, Germany. [email protected] FAU - Arck, P C
PMID: 11641256 [PubMed - indexed for MEDLINE]
It has long been suspected that stress can cause hair loss, although convincing evidence of this has been unavailable. Here, we show that in mice sonic stress significantly increased the number of hair follicles containing
apoptotic cells and inhibited intrafollicular keratinocyte proliferation in situ. Sonic stress also significantly increased the number of activated perifollicular macrophage clusters and the number of degranulated mast cells, whereas it
down-regulated the number of intraepithelial gd T lymphocytes. These stress-induced immune changes could be mimicked by injection of the neuropeptide substance P in nonstressed mice and were abrogated by a selective
substance P receptor antagonist in stressed mice. We conclude that stress can indeed inhibit hair growth in vivo, probably via a substance P-dependent activation of macrophages and/or mast cells in the context of a brain-hair
follicle axis.
Noggin is required for induction of the hair follicle growth phase in postnatal skin.
Botchkarev VA, Botchkareva NV, Nakamura M, Huber O, Funa K, Lauster R, Paus R, Gilchrest BA
FASEB J 2001 Oct;15(12):2205-14.
Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts 02118, USA. [email protected] FAU - Botchkarev, V A
PMID: 11641247 [PubMed - indexed for MEDLINE]
During postnatal development, the hair follicle (HF) shows cyclic activity with periods of relative resting, active growth (anagen), and regression. We demonstrate that similar to the HF induction in embryonic skin, initiation of a
new hair growth phase in postnatal skin requires neutralization of the inhibitory activity of bone morphogenetic protein 4 (BMP4) by the BMP antagonist noggin. In the resting HF, BMP4 mRNA predominates over noggin in the
epithelium and mesenchyme, and the BMP receptor IA is prominently expressed in the follicular germ. Anagen development is accompanied by down-regulation of the BMP4 and increased noggin mRNA in the HF. Furthermore,
administration of noggin protein induces new hair growth phase in postnatal telogen skin in vivo. In contrast, BMP4 induces selective arrest of anagen development in the non-tylotrich (secondary) HF. As a hair growth inducer,
noggin increases Shh mRNA in the HF whereas BMP4 down-regulates Shh. This suggests that modulation of BMP4 signaling by noggin is essential for hair growth phase induction in postnatal skin and that the hair growthinducing effect of noggin is mediated, at least in part, by Shh.
High-dose proinflammatory cytokines induce apoptosis of hair bulb keratinocytes in vivo.
Ruckert R, Lindner G, Bulfone-Paus S, Paus R
Br J Dermatol 2000 Nov;143(5):1036-9.
Institute of Immunology, Benjamin Franklin Medical Center, Free University Berlin, Berlin, Germany. FAU - Ruckert, R
PMID: 11069516 [PubMed - indexed for MEDLINE]
BACKGROUND: Hair loss following skin inflammation may in part be mediated by keratinocyte (KC) apoptosis. While the effects of different cytokines or other apoptosis stimulating agents such as interferon (IFN)-gamma or
tumour necrosis factor (TNF)-alpha on KC apoptosis in vitro have been addressed in several studies, little is known about the effects of proinflammatory cytokines on KC apoptosis in vivo. OBJECTIVES: To study the effects of
intradermally injected TNF-alpha, interleukin (IL)-1beta and IFN-gamma on KC apoptosis in the back skin of C57BL/6 mice. METHODS: Apoptosis in epidermal and hair bulb KCs was analysed by immunohistology using TUNEL
staining. RESULTS: Injection of TNF-alpha induced a significantly higher number of apoptotic cells within the epidermis than vehicle; all three proinflammatory cytokines together further increased their number. Intrafollicular hair
bulb KCs were much more susceptible to apoptosis induction by TNF-alpha or IL-1beta; their injection significantly upregulated apoptosis after 6 h, which was further increased after 24 h. The combination of all cytokines together
accelerated intrafollicular apoptosis after 6 h by doubling the number of apoptotic cells per hair bulb, compared with the effects of TNF-alpha or IL-1beta alone. CONCLUSIONS: These data suggest that programmed cell death of
proliferating KCs in vivo can be induced by proinflammatory cytokines.
A role for p75 neurotrophin receptor in the control of apoptosis-driven hair follicle regression.
Botchkarev VA, Botchkareva NV, Albers KM, Chen LH, Welker P, Paus R
FASEB J 2000 Oct;14(13):1931-42.
*Department of Dermatology, Charite, Humboldt University, Berlin, Germany. FAU - Botchkarev, V A
PMID: 11023977 [PubMed - indexed for MEDLINE]
To examine the mechanisms that underlie the neurotrophin-induced, apoptosis-driven hair follicle involution (catagen), the expression and function of p75 neurotrophin receptor (p75NTR), which is implicated in apoptosis control,
were studied during spontaneous catagen development in murine skin. By RT-PCR, high steady-state p75NTR mRNA skin levels were found during the anagen-catagen transition of the hair follicle. By immunohistochemistry,
p75NTR alone was strongly expressed in TUNEL+/Bcl2- keratinocytes of the regressing outer root sheath, but both p75NTR and TrkB and/or TrkC were expressed by the nonregressing TUNEL-/Bcl2+ secondary hair germ
keratinocytes. To determine whether p75NTR is functionally involved in catagen control, spontaneous catagen development was compared in vivo between p75NTR knockout (-/-) and wild-type mice. There was significant
catagen retardation in p75NTR knockout mice as compared to wild-type controls (P<0.05). Instead, transgenic mice-overexpressing NGF (promoter: K14) showed substantial acceleration of catagen (P<0.001). Although NGF,
brain-derived neurotrophic factor (BDNF), and neurotrophin 3 (NT-3) accelerated catagen in the organ-cultured skin of C57BL/6 mice, these neurotrophins failed to promote catagen development in the organ-cultured p75NTR
null skin. These findings suggest that p75NTR signaling is involved in the control of kerotinocyte apoptosis during catagen and that pharmacological manipulation of p75NTR signaling may prove useful for the treatment of hair
disorders that display premature entry into catagen.
Patterns of hairless (hr) gene expression in mouse hair follicle morphogenesis and cycling.
Panteleyev AA, Paus R, Christiano AM
Am J Pathol 2000 Oct;157(4):1071-9.
Departments of Dermatology and Genetics and Development, Columbia University, New York, USA. FAU - Panteleyev, A A
PMID: 11021810 [PubMed - indexed for MEDLINE]
The hr (hairless) gene encodes a putative transcription factor with restricted expression in the skin and brain. Mutations in the hr locus cause papular atrichia in humans and complete hair loss in mice and other mammals. To
further elucidate the role of hr in skin biology, and to identify potential target cells for hr regulation, we studied hr mRNA localization during hair follicle (HF) morphogenesis and cycling in normal C57BL/6J mice. In situ
hybridization revealed that hr expression was present in the suprabasal cell layers of the epidermis, whereas the basal and highly differentiated keratinocytes of the granular layer were hr-negative. During the early stages of HF
morphogenesis, hr mRNA was detected in the developing hair peg. Later, it became concentrated in the HF infundibulum, in the HF matrix, and in the inner root sheath (IRS), whereas the dermal papilla (DP) and outer root
sheath were consistently hr mRNA-negative. During catagen, hr gene expression gradually declined in the regressing IRS, shortly but dramatically increased in the zone of developing club hair, and became up-regulated in the
epithelial cells adjacent to the DP. The co-localization of hr mRNA with the site of the morphological defects in mutant skin implicates hr as a key factor in regulating basic cellular processes during catagen, including club hair
formation, maintenance of DP-epithelial integrity, IRS disintegration, and keratinocyte apoptosis in the HF matrix.
The skin POMC system (SPS). Leads and lessons from the hair follicle.
Paus R, Botchkarev VA, Botchkareva NV, Mecklenburg L, Luger T, Slominski A
Ann N Y Acad Sci 1999 Oct 20;885:350-63.
Department of Dermatology, Charite, Humboldt-University, Berlin, Germany. [email protected] FAU - Paus, R
PMID: 10816666 [PubMed - indexed for MEDLINE]
Human and murine skin are prominent extrapituitary sources and targets for POMC products. The expression of, for example, ACTH, alpha-MSH, beta-endorphin, and MC-1-receptors fluctuates during synchronized hair follicle
cycling in C57BL/6 mice. Since hair growth can be induced by ACTH injections in mice and mink, and since high doses of MSH peptides modulate epidermal and/or follicle keratinocyte proliferation in murine skin organ culture,
some POMC products may operate as locally generated growth modulators, in addition to their roles in cutaneous pigment and immunobiology. Intrafollicularly generated ACTH and alpha-MSH as well as their cognate receptors
may assist in the maintenance of the peculiar immune privilege of the anagen hair bulb. Possibly, they are also involved in the development of the follicle pigmentary unit, with whose generation their expression coincides. Given
that murine skin also expresses (in a hair-cycle-dependent way) CRH and CRH-R, which control pituitary POMC expression and in view of the fact that CRH arrests follicles in telogen, this suggests the existence of a local skin
POMC system (SPS). This may be an integral component of cutaneous stress response-systems, and may most instructively be studied using the murine hair cycle as a model.
Cutaneous expression of CRH and CRH-R. Is there a "skin stress response system?".
Slominski AT, Botchkarev V, Choudhry M, Fazal N, Fechner K, Furkert J, Krause E, Roloff B, Sayeed M, Wei E, Zbytek B, Zipper J, Wortsman J, Paus R
Ann N Y Acad Sci 1999 Oct 20;885:287-311.
Department of Pathology, Loyola University, Maywood, Illinois, USA. [email protected] FAU - Slominski, A T
PMID: 10816662 [PubMed - indexed for MEDLINE]
The classical neuroendocrine pathway for response to systemic stress is by hypothalamic release of corticotropin releasing hormone (CRH), subsequent activation of pituitary CRH receptors (CRH-R), and production and release
of proopiomelanocortin (POMC) derived peptides. It has been proposed that an equivalent to the hypothalamic-pituitary-adrenal axis functions in mammalian skin, in response to local stress (see Reference 1). To further define
such system we used immunocytochemistry, RP-HPLC separation, and RIA techniques, in rodent and human skin, and in cultured normal and malignant melanocytes and keratinocytes. Production of mRNA for CRH-R1 was
documented in mouse and human skin using RT-PCR and Northern blot techniques; CRH binding sites and CRH-R1 protein were also identified. Addition of CRH to immortalized human keratinocytes, and to rodent and human
melanoma cells induced rapid, specific, and dose-dependent increases in intracellular Ca2+. The latter were inhibited by the CRH antagonist alpha-helical-CRH(9-41) and by the depletion of extracellular calcium with EGTA. CRH
production was enhanced by ultraviolet light radiation and forskolin (a stimulator for intracellular cAMP production), and inhibited by dexamethasone. Thus, evidence that skin cells, both produce CRH and express functional CRHR1, supports the existence of a local CRH/CRH-R neuroendocrine pathway that may be activated within the context of a skin stress response system.
The human hair follicle immune system: cellular composition and immune privilege.
Christoph T, Muller-Rover S, Audring H, Tobin DJ, Hermes B, Cotsarelis G, Ruckert R, Paus R
Br J Dermatol 2000 May;142(5):862-73.
Department of Dermatology, University Hospital Eppendorf, University of Hamburg, Martinistrasse 52, D-20246 Hamburg, Germany. FAU - Christoph, T
PMID: 10809841 [PubMed - indexed for MEDLINE]
The immunology of the hair follicle, its relationship with the 'skin immune system' and its role in hair diseases remain biologically intriguing and clinically important. In this study, we analysed the immunoreactivity patterns of 15
immunodermatological markers to determine the cellular composition and immune privilege of the human hair follicle immune system in anagen VI (growth phase). The most prominent cells located in or around the hair follicle
were Langerhans cells, CD4+ or CD8+ T cells, macrophages and mast cells, whereas B cells, natural killer cells and gammadelta T cells were found very rarely. Langerhans cells (CD1a+, major histocompatibility complex, MHC
class II+), and T cells (CD4+ or CD8+) were predominantly distributed in the distal hair follicle epithelium, whereas macrophages (CD68+, MHC class II+) and mast cells (Giemsa+) were located in the perifollicular connective
tissue sheath. Transmission electron microscopy confirmed low numbers of immune cells in the proximal hair follicle epithelium, and very few macrophages and Langerhans cells were seen in the dermal papilla. Melanophages
were observed in the connective tissue sheath and dermal papilla. MHC class I (HLA-A, -B, -C) and beta2-microglobulin immunoreactivity was found on most skin cells, but was substantially reduced on isthmus keratinocytes and
virtually absent in the proximal hair follicle epithelium. Apart from the absence of Fas ligand immunoreactivity, the sharply reduced numbers of T cells and Langerhans cells, and the virtual absence of MHC class I expression all
suggest that the anagen proximal hair follicle constitutes an area of immune privilege within the hair follicle immune system, whose collapse may be crucial for the pathogenesis of alopecia areata.
Active hair growth (anagen) is associated with angiogenesis.
Mecklenburg L, Tobin DJ, Muller-Rover S, Handjiski B, Wendt G, Peters EM, Pohl S, Moll I, Paus R
J Invest Dermatol 2000 May;114(5):909-16.
Department of Dermatology, University Hospital Eppendorf, University of Hamburg, Germany. FAU - Mecklenburg, L
PMID: 10771470 [PubMed - indexed for MEDLINE]
After the completion of skin development, angiogenesis, i.e., the growth of new capillaries from pre-existing blood vessels, is held to occur in the skin only under pathologic conditions. It has long been noted, however, that hair
follicle cycling is associated with prominent changes in skin perfusion, that the epithelial hair bulbs of anagen follicles display angiogenic properties, and that the follicular dermal papilla can produce angiogenic factors. Despite
these suggestive observations, no formal proof is as yet available for the concept that angiogenesis is a physiologic event that occurs all over the mature mammalian integument whenever hair follicles switch from resting
(telogen) to active growth (anagen). This study uses quantitative histomorphometry and double-immunohistologic detection techniques for the demarcation of proliferating endothelial cells, to show that synchronized hair follicle
cycling in adolescent C57BL/6 mice is associated with substantial angiogenesis, and that inhibiting angiogenesis in vivo by the intraperitoneal application of a fumagillin derivative retards experimentally induced anagen
development in these mice. Thus, angiogenesis is a physiologic event in normal postnatal murine skin, apparently is dictated by the hair follicle, and appears to be required for normal anagen development. Anagen-associated
angiogenesis offers an attractive model for identifying the physiologic controls of cutaneous angiogenesis, and an interesting system for screening the effects of potential antiangiogenic drugs in vivo.
Control of murine hair follicle regression (catagen) by TGF-beta1 in vivo.
Foitzik K, Lindner G, Mueller-Roever S, Maurer M, Botchkareva N, Botchkarev V, Handjiski B, Metz M, Hibino T, Soma T, Dotto GP, Paus R
FASEB J 2000 Apr;14(5):752-60.
Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA. Department of Dermatology, University Hospital Eppendorf, University of Hamburg,
D-20246 Hamburg, Germany. Departme. FAU
PMID: 10744631 [PubMed - indexed for MEDLINE]
The regression phase of the hair cycle (catagen) is an apoptosis-driven process accompanied by terminal differentiation, proteolysis, and matrix remodeling. As an inhibitor of keratinocyte proliferation and inductor of keratinocyte
apoptosis, transforming growth factor beta1 (TGF-beta1) has been proposed to play an important role in catagen regulation. This is suggested, for example, by maximal expression of TGF-beta1 and its receptors during late
anagen and the onset of catagen of the hair cycle. We examined the potential involvement of TGF-beta1 in catagen control. We compared the first spontaneous entry of hair follicles into catagen between TGF-beta1 null mice
and age-matched wild-type littermates, and assessed the effects of TGF-beta1 injection on murine anagen hair follicles in vivo. At day 18 p.p., hair follicles in TGF-beta1 -/- mice were still in early catagen, whereas hair follicles of
+/+ littermates had already entered the subsequent resting phase (telogen). TGF-beta1-/- mice displayed more Ki-67-positive cells and fewer apoptotic cells than comparable catagen follicles from +/+ mice. In contrast, injection
of TGF-beta1 into the back skin of mice induced premature catagen development. In addition, the number of proliferating follicle keratinocytes was reduced and the number of TUNEL + cells was increased in the TGF-beta1treated mice compared to controls. Double visualization of TGF-beta type II receptor (TGFRII) and TUNEL reactivity revealed colocalization of apoptotic nuclei and TGFRII in catagen follicles. These data strongly support that
TGF-beta1 ranks among the elusive endogenous regulators of catagen induction in vivo, possibly via the inhibition of keratinocyte proliferation and induction of apoptosis. Thus, TGF-betaRII agonists and antagonists may provide
useful therapeutic tools for human hair growth disorders based on premature or retarded catagen development (effluvium, alopecia, hirsutism).
Intercellular adhesion molecule-1 and hair follicle regression.
Muller-Rover S, Bulfone-Paus S, Handjiski B, Welker P, Sundberg JP, McKay IA, Botchkarev VA, Paus R
J Histochem Cytochem 2000 Apr;48(4):557-68.
Centre for Cutaneous Research, University of London, London, United Kingdom. FAU - Muller-Rover, S
PMID: 10727297 [PubMed - indexed for MEDLINE]
Although the intercellular adhesion molecule-1 (ICAM-1) is recognized for its pivotal role in inflammation and immune responses, its role in developmental systems, such as the cyclic growth (anagen) and regression (catagen) of
the hair follicle, remains to be explored. Here we demonstrate that ICAM-1 expression in murine skin is even more widespread and more developmentally regulated than was previously believed. In addition to endothelial cells,
selected epidermal and follicular keratinocyte subpopulations, as well as interfollicular fibroblasts, express ICAM-1. Murine hair follicles express ICAM-1 only late during morphogenesis. Thereafter, morphologically identical
follicles markedly differ in their ICAM-1 expression patterns, which become strikingly hair cycle-dependent in both intra- and extrafollicular skin compartments. Minimal ICAM-1 and leukocyte function-associated (LFA-1) protein
and mRNA expression is observed during early anagen and maximal expression during late anagen and catagen. Keratinocytes of the distal outer root sheath, fibroblasts of the perifollicular connective tissue sheath, and
perifollicular blood vessels exhibit maximal ICAM-1 immunoreactivity during catagen, which corresponds to changes of LFA-1 expression on perifollicular macrophages. Finally, ICAM-1-deficient mice display significant catagen
acceleration compared to wild-type controls. Therefore, ICAM-1 upregulation is not limited to pathological situations but is also important for skin and hair follicle remodeling. Collectively, this suggests a new and apparently
nonimmunological function for ICAM-1-related signaling in cutaneous biology.
Chronobiology of the hair follicle: hunting the " hair cycle clock".
Paus R, Muller-Rover S, Botchkarev VA
J Investig Dermatol Symp Proc 1999 Dec;4(3):338-45.
Department of Dermatology, University Hospital Eppendorf, University of Hamburg, Germany. [email protected] FAU - Paus, R
PMID: 10674393 [PubMed - indexed for MEDLINE]
The hair follicle (HF) is the only mammalian organ that undergoes life-long, cyclic transformations from long stages of growth (anagen), via rapid, apoptosis-driven organ involution (catagen) to a stage of relative "resting"
(telogen). The controls that underlie these transformations clearly reside in and/or around the HF itself, and are likely to reflect - essentially autonomous, yet highly manipulable - changes in the local signalling milieu of e.g., hair
growth-modulatory growth factors, cytokines, hormones and adhesion molecules. Yet the molecular nature and organization of the "hair cycle clock" (HCC) that drives these cyclic switches in the local signalling milieu remain
obscure, and there is not even a fully satisfactory theory of hair cycle control. Since deciphering of the HCC is of paramount clinical importance, and since corresponding working hypotheses are badly needed to guide the design
of more incisive experiments that identify the elusive central "oscillator" mechanism behind the HCC, we discuss basic requirements any convincing HCC theory should meet. After arguing that at least four distinct timing devices
underlie HF chronobiology ("morphogenesis clock", "cycling inducer", "desynchronizer", and the actual HCC), previously proposed HCC theories are briefly and critically reviewed. In the light of intriguing regulatory similarities
between the HCC and the cell cycle machinery, we suggest here that the HCC may be driven by autonomous, cell cycle-coupled secretory activities of the HF mesenchyme, namely by changes in the G0/G1-associated secretion
of "papilla morphogens" by dermal papilla fibroblasts. Hopefully, this provocative hypothesis will encourage the proposition of novel, comprehensive HCC theories.
The fate of hair follicle melanocytes during the hair growth cycle.
Tobin DJ, Slominski A, Botchkarev V, Paus R
J Investig Dermatol Symp Proc 1999 Dec;4(3):323-32.
Department of Biomedical Sciences, University of Bradford, UK. [email protected] FAU - Tobin, D J
PMID: 10674391 [PubMed - indexed for MEDLINE]
The fate of the follicular pigmentary unit during the hair growth cycle has long been one of the great enigmas of both hair follicle and pigment cell biology. Although melanocytes are distributed in several different compartments of
the anagen hair follicle, melanogenically active cells are located only in the hair bulb, where they are directly involved in hair shaft pigmentation. These pigment cells are readily detectable only when they become melanogenically
active during anagen III of the hair growth cycle. Thus, their status during hair follicle regression (catagen), when melanogenesis is switched off, until they re-appear again as pigment-producing cells in the anagen III hair follicle,
has remained poorly defined. Historically, it has been proposed that hair bulb melanocytes adopt a self-perpetuating, catagen-resistant strategy of de-differentiation during hair follicle regression and re-differentiation upon entry
into a new anagen phase; however, this explanation remains problematic in the absence of evidence for de-differentiation/re-differentiation plasticity in most nonmalignant cell systems.
Immunology of the hair follicle: a short journey into terra incognita.
Paus R, Christoph T, Muller-Rover S
J Investig Dermatol Symp Proc 1999 Dec;4(3):226-34.
Department of Dermatology, Charite, Humboldt-University Berlin, Germany. [email protected] FAU - Paus, R
PMID: 10674372 [PubMed - indexed for MEDLINE]
This paper delineates briefly why the immunology of the hair follicle matters (e.g., anti-infection defense, hair growth control by immunomodulatory agents, sequestration of follicular autoantigens), and which open key questions
await clarification. We then focus on the murine hair follicle immune system (HIS) and its immune privilege. We show how the murine HIS is gradually constructed during hair follicle morphogenesis, and how it is transformed
during hair follicle cycling. Key characteristics of the HIS are summarized, such as the absence of MHC class I expression in the anagen hair bulb and the very restricted distribution of antigen-presenting cells and intraepithelial T
cells to the distal outer root sheath, which also expresses nonclassical MHC class Ib molecules. The interconnections between the HIS and the skin immune system (SIS) and potential hair growth-modulatory roles of mast cells
and macrophages are addressed, and very recent findings on the human HIS are summarized. The paper closes by sketching immunobiologic, clinical, and pharmacologic perspectives in trichoimmunology that deserve the
attention of immunologists, dermatologists, and hair biologists alike.