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1
* 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;
Department of Dermatology, Charité, Humboldt University, Berlin, Germany;
§ Centre for Cutaneous Research, Queen Mary College, University of London, London, U.K;
¶ Department of Dermatology, Johannes-Gutenberg University, Mainz, Germany;
** Department of Dermatology, Boston University, Boston, Massachusetts 02118, USA; and
Shiseido Research Center, Yokohama, Japan
1Correspondence: Department of Dermatology, UKE, University of Hamburg, Martinistr. 52, D-20246 Hamburg, Germany. E-mail: paus{at}uke.uni-hamburg.de
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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Key Words: in vivo • apoptosis • TGF-ß receptor
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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2
3
4
5
6
7)
. Although the morphological changes associated with
the hair cycle are well described, the underlying molecular controls
that terminate anagen and initiate catagen are still poorly understood
(5
, 8
9
10
11
12)
. Recent studies have implicated transforming
growth factor ß1 (TGF-ß1) in the control of catagen
(13
14
15)
.
Members of the TGF-ß family of growth factors are regulators of cell
growth, apoptosis, and differentiation and act as powerful morphogens
during embryogenesis (16
, 17)
. The three mammalian TGF-ß
isoforms TGF-ß1, 2, and 3 share a 80% homology and exhibit many
similar activities in vitro, whereas the strikingly
nonoverlapping defects observed in the knockout mice for individual
TGF-ß isoforms illustrate their distinct functions in vivo
(18)
. TGF-ß1 knockout mice die ~3–4 wk after birth
due to a wasting syndrome accompanied by multifocal inflammation
(19
, 20)
, whereas disruption of the TGF-ß 2 or ß 3
gene results in developmental defects, which are incompatible with life
after birth (21
, 22)
. All TGF-ß isoforms inhibit
keratinocyte proliferation and stimulate synthesis and degradation of
extracellular matrix proteins by fibroblasts (23
24
25)
.
TGF-ß1 induces apoptosis in keratinocytes (26)
, whereas
TGF-ß3 protects keratinocytes against TPA-induced cell death
(27)
, raising the possibility that TGF-ß1 is involved in
apoptosis-driven catagen development. However, evidence that TGF-ß1
really is a catagen inductor in vivo is still lacking.
TGF-ß isoforms trigger their signal through the same
heteromeric complexes of type I and type II serine-threonine kinase
receptors and through the same intracellular downstream pathway via
Smad 2 and 3 proteins (28
, 29)
. Signal transduction
requires complex formation of both receptors, but only the type II
receptor has been shown to be able to bind ligands; thus,
colocalization of TGF-ß receptors is critically important for
appropriate TGF-ß signaling (30)
.
Several studies have investigated the expression of TGF-ß
isoforms and their receptors during the murine hair cycle. Transcript
levels of TGF-ß receptor type I and type II and their high-affinity
ligands TGF-ß1 and 3 decline during anagen and are maximal during the
anagen-catagen (8
, 13
, 15)
. Immunohistochemical analysis
revealed that TGF-ß type I and II receptor proteins are expressed in
the outer root sheath (ORS), correlating with the increasing length of
the inner root sheath (IRS), and in a subpopulation of matrix cells
during anagen; this expression pattern rapidly disappeared with the
regressing IRS during the catagen-telogen transformation
(13)
. Also, follicular expression of TGF-ß 1 and
TGF-ß3 are hair cycle dependent (15)
. TGF-ß3 could be
detected in the connective tissue sheath, whereas TGF-ß 1 was seen in
the IRS during the anagen-catagen transformation (31)
.
These data suggest that the main target cells for TGF-ß are localized
primarily in the ORS of the hair follicle during late anagen and
catagen. Functionally, this concept has received strong support by the
in vitro observation that isolated, organ-cultured rat and
human anagen hair follicles are growth inhibited by TGF-ß1 and can be
induced to enter a regression process that resembles early stages of a
catagen-like transformation in several aspects (14
, 32)
.
This study, therefore, explores the functions of TGF-ß1 in catagen regulation in vivo by analysis of mice with a targeted disruption of the TGF-ß1 gene and by studying the effect of TGF-ß1 protein injection on hair follicle regression in vivo. Our data support the hypothesis that TGF-ß1 is involved in the regulation of catagen, possibly by the induction of apoptosis and the inhibition of proliferation of hair follicle keratinocytes positive for TGF-ß type II receptor (TGFRII) expression.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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, heterozygous, and wild-type littermates from
heterozygous TGF-ß 1 breeding pairs were killed at day 18 postpartum
(p.p.) by cervical dislocation. Homozygous knockout, heterozygous, and
control mice were confirmed by polymerase chain reaction analysis of
their tail DNA with oligonucleotide primers specific for wild-type and
disrupted alleles (20)
. Tissue was harvested from the neck
region of the back skin (n=5/group) and fixed in formalin
for routine histology.
Six- to 9-wk-old syngenic, female C57BL/6 mice in telogen stage of the
hair cycle (33)
were purchased from Charles River
(Sulzfeld, Germany). Mice were housed in community cages with 12 h
light periods and fed water and mouse chow ad libitum.
Hair cycle induction and TGF-ß1 treatment
Anagen was induced in the back skin of C57BL/6 adolescent mice
in telogen phase of the cycle by depilation as described
(33)
, which induces a highly predictable development of
anagen follicles. Between days 17 and 19 postdepilation (p.d.), anagen
hair follicles regress spontaneously and enter catagen thereafter
(4
, 34)
. Recombinant human TGF-ß1 (0.3 µg; R&D
systems, Minneapolis, Minn.) was injected subcutaneous (s.c.) twice
daily on days 13, 14, and 15 after depilation in the tail region of the
back skin. Tissue was harvested at day 18 p.d. from 10 mice/group
and fixed in formalin.
Histology and histomorphometry
Paraffin sections were routinely stained by H&E or Giemsa.
Slides were screened for longitudinal hair follicles (HF) ,and the hair
cycle stage of each HF was assessed and classified by morphological
criteria and assigned to their respective hair cycle stages, following
precisely a described technique of quantitative histomorphometry of
catagen development (7
, 35)
. The hair cycle score (HCS)
was assessed and calculated as described (7)
.
Immunohistochemistry
Immunohistochemical detection of TGF-ß1
A rabbit polyclonal antibody to TGF-ß1 was purchased from
Santa Cruz (Santa Cruz Biotechnology, Santa Cruz, Calif.). To eliminate
nonspecific binding of antibody to epidermal and follicular keratin,
anti-TGF-ß1 antibody diluted to the working concentration (2.5
µg/ml) was incubated with 100 mg/ml human keratin powder (extracted
from human hair bearing skin) in phosphate-buffered saline (PBS)
containing 3% bovine serum albumin with a vigorous shaking at 4°C
overnight. After centrifugation, supernatants were collected and used
for immunohistochemical staining. Paraffin-embedded tissue sections
were deparaffinized, rehydrated, and equilibrated in PBS for 10 min at
room temperature. For anti-TGF-ß1 antibody immunostaining, tissue
sections were moderately digested with 10 mg/ml proteinase K
(Nakaraitesque, Tokyo, Japan) in PBS for 30 min at 37°C. After
blocking with 10% normal goat serum for 20 min at room temperature,
sections were incubated with keratin-treated anti-TGF-ß1 antibody
overnight at 4°C. Sections were incubated with DAKO EnVision+
(peroxidase, rabbit) (DAKO, Carpinteria, Calif.) as a secondary
antibody for 20 min at room temperature. Diaminobenzidine (KPL Inc.,
Gaithersburg, Md.) was used as a color-developing reagent in
Tris-buffer (pH 7.6) containing 0.01%
H2O2. Sections were
counterstained by hematoxylin and mounted with organic mounting medium.
Double immunodetection of TUNEL-positive cells and Ki-67
To evaluate apoptotic cells, we used an established,
commercially available TUNEL kit (ApopTag, Oncor, Gaithersburg, Md.) as
described before (4)
. For double immunofluorescence
detection of TUNEL-positive cells and Ki-67-IR, the protocol for the
TUNEL technique was combined with the manufacturer’s protocol for
Ki-67-immunohistochemistry. Briefly, 4 µm sections were
deparaffinized and heated in citrate buffer pH 6.0 for 5 min at 100°C
and then incubated with rabbit anti-Ki-67 antiserum, followed by an
incubation with digoxigenin-dUTP in the presence of TdT. Subsequently,
TUNEL-positive cells were visualized by antidigoxigenin FITC-conjugated
F(ab)2 fragments, Ki-67-IR was detected by goat
anti-rabbit TRITC-conjugated antibody, and sections were counterstained
by Hoechst 33342. Negative controls for the TUNEL staining were made by
omitting TdT, according to the manufacturer’s protocol. Positive TUNEL
controls were run, as described (4)
, by comparison with
tissue sections from the thymus of infantile mice, which display a high
degree of spontaneous thymocyte apoptosis .
Double immunodetection of TUNEL-positive cells and
TGFß-RII-IR
To double visualize apoptotic cells and TGFß-RII-IR, we used a
previously established protocol (4)
. Briefly,
TUNEL-positive cells were detected using commercially available kit
(ApopTag, Oncor) with antidigoxigenin FITC-conjugated
F(ab)2 fragments, and TGFß-RII-IR was
visualized with the application of corresponding primary rabbit
antiserum overnight at room temperature (1:100, Santa Cruz
Biotechnology), followed by secondary goat anti-rabbit TRITC-conjugated
antibody (Jackson Immuno-Research Inc., West Grove, Pa.; 1:200, 30 min,
37°C) following previously developed basic protocols
(36)
. Sections were counterstained by Hoechst 33342.
Negative controls for the TUNEL staining were performed by omitting
TdT, according to the manufacturer’s protocol. Sections from the
thymus of infantile mice, which display a high degree of spontaneous
thymocyte apoptosis, were used as a positive TUNEL control as described
(37)
. After washing in TBS, all sections were mounted with
immunomount medium (Shandon, Pittsburgh, Pa.). Sections were examined
under a Zeiss Axioscope microscope, using the appropriate
excitation-emission filter systems for the fluorescence induced by
Hoechst 33342, FITC, or TRITC. Photodocumentation was done
using a digital image analysis system (ISIS Metasystems, Altlussheim,
Germany).
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RESULTS AND DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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, 27)
, we wanted to explore where in the regressing hair follicle
TGF-ß1 is expressed and where it may induce apoptosis associated with
this key phase of the hair cycle (44
, 45)
. As a first
indication, the expression of TGF-ß1 protein during the
depilation-induced hair cycle was studied (Fig. 1
).
|
In telogen, TGF-ß1 could not be detected anywhere in the hair
follicle, and during early anagen TGF-ß1 was expressed only in the
bulge region of the ORS below the sebaceous gland. In more advanced
anagen stages TGF-ß1 expression increased and intense immunostaining
for TGF-ß1 was seen in the ORS and epithelial strand during late
anagen and catagen stages (Fig. 1)
. Contrary to our earlier results
(31)
, we could not detect any immunohistochemical staining
for TGF-ß1 in the IRS of the hair follicle. The absence of TGF-ß1
in the IRS most likely reflects differences in the staining protocol
and the primary antibodies used in the two studies. In the current
paper, we show a more careful analysis of TGF-ß1 expression in
longitudinally cut hair follicles at different stages of the hair
cycle. We repeated the immunohistochemical analysis of TGF-1 with
different antibodies and newly cut skin sections of better quality.
These sections contain more longitudinally cut hair follicles, which is
necessary to reveal sufficient details of the TGFß1 protein
localization within the hair follicle. The data presented in this study
show maximal TGF-ß1 protein expression during late anagen and early
catagen; this correlates well with our previous finding that TGF-ß1
transcripts are up-regulated during late anagen and onset of catagen
(15)
.
The immunodetection of TGF-ß1 during the hair cycle revealed
the strongest expression during late anagen and the onset of catagen in
cells of the ORS and epithelial strand, i.e., in the epithelial residue
of the regressing hair bulb during catagen. To detect potential target
cells of TGF-ß1 in the hair follicle, we performed a double
immunovisualization of TGFß-RII and TUNEL (Fig. 2a, b
). TGF-ßRII expressing cells were found in the proximal
and central region of the ORS during late anagen and catagen, as
described previously in detail (13)
.
|
The double staining revealed that in midcatagen hair follicles (catagen
III-IV), single TGFß-RII immunoreactive keratinocytes in the central
ORS contain TUNEL-positive nuclei (Fig. 2a
). In addition,
during late catagen (VI), a colocalization of TGFß-RII
immunoreactivity and TUNEL-positive nuclei was also seen in many
keratinocytes of the regressing epithelial strand (Fig. 2b
).
This raises the possibility that TGF-ßRII-mediated signaling was
somehow related to the occurrence of apoptosis in these cells.
Obviously, not all keratinocytes in the regressing hair follicle that
express TGF-ßRII undergo apoptosis. These data show that TGF-ß1 is
expressed maximal in the ORS and epithelial strand during catagen
development and that TUNEL-positive cells in the hair follicle are also
positive for TGF-ßRII, indicating that TGF-ß1 may indeed induce
apoptosis in selected keratinocytes of the ORS and epithelial strand
during catagen.
Catagen development is delayed in TGF-ß1-deficient mice
Maximal expression of TGF-ß1 during the late anagen and onset of
catagen and colocalization of TGFRII and apoptotic nuclei strongly
suggest an involvement of TGF-ß1 in catagen development. To test
whether this factor is indeed required for catagen induction, we
examined catagen development during initiation of the first hair cycle
in TGF-ß1-deficient mice compared to their heterozygous (-/+) and
wild-type (+/+) littermates. Mice with a disruption of the TGF-ß1
gene die ~3–4 wk after birth due to a multi-inflammatory wasting
syndrome (20)
. Since HF enter catagen spontaneously
between days 17 and 19 p.p., we harvested back skin from day
18 p.p. mice and compared their hair cycle stages by quantitative
histomorphometry. This revealed that ~50% of the HF in TGF-ß1-/-
mice were still in anagen at day 18 p.p., whereas 40% of HF in
wild-type littermates and 25% of HF in heterozygous mice had already
entered telogen as the end point of the hair cycle (Fig. 3A
). In contrast, none of the HF in TGF-ß1 -/- mice had
already reached this end point at day 18 p.p. This was confirmed
by calculation of the hair cycle score (HCS), which allows one to
quantitatively assess and compare the full range of catagen stages
among experimental groups. The HCS showed the highest values for +/+
and the lowest for -/- mice, with ± mice occupying an
intermediate position (Fig. 3B
). This reveals that catagen
development in homozygous TGF-ß1 knockout mice was significantly
retarded compared to wild-type (wt) littermates.
|
To determine any differences in proliferation and apoptosis during
catagen development between these mice, Ki-67/TUNEL double staining was
performed. Whereas at day 18 p.p., many Ki-67 positive but almost
no apoptotic cells are detectable in the hair bulbs of anagen follicles
in TGF-ß1 null mice (Fig 2c
), hair follicles of
heterozygous mice showed Ki-67 and TUNEL+ fragments in the hair bulb of
early catagen HF (Fig. 2d
). Wild-type animals showed hair
follicles already in late catagen, and telogen HF exhibited only TUNEL+
nuclei and scattered Ki-67-positive cells (Fig. 2e
). For
statistical analysis, we counted Ki-67 + cells of identical catagen
stages in the different phenotypes and detected significantly more
proliferating cells in the hair bulb of TGF-ß1 null mice compared to
wild-type animals (Fig. 4
), whereas heterozygous mice had a similar number of Ki-67 + cells as wt
HF (Fig. 4)
.
|
Thus, TGF-ß1-deficient mice have a significantly prolonged anagen
phase compared to their wild-type and heterozygous littermates. This
finding is even more striking since it is known that infections and
weight loss as observed in TGF-ß1-deficient mice at this point
usually cause premature hair loss (44
, 45
, 46)
. In
addition, TGF-ß1 null mice show a significantly higher number of
proliferating and a lower number of apoptotic cells in the hair bulb of
anagen VI and early catagen hair follicles. This is in line with
reports that TGF-ß1 inhibits keratinocyte proliferation (23
, 24)
and induces keratinocyte apoptosis (26
, 27)
.
Overexpression of TGF-ß1 indeed results in a shiny, thin atrophic
epidermis with a reduced number of hair follicles, and BrdU
incorporation is almost completely shut down in epidermal and
follicular keratinocytes of these transgenic mice (38)
. In
contrast, dominant-negative TGF-ßRII overexpressing transgenic mice
have a 2.5-fold increased BrdU labeling index in the epidermis
(39)
. Therefore, both the increased proliferation and the
reduced keratinocyte apoptosis observed in the hair bulbs of TGF-ß1
null mice (Fig. 2c
2d
, Fig. 5
) suggest that TGF-ß1 is required for timely entry into the catagen
phase.
|
TGF-ß1 treatment results in premature catagen development,
associated with reduced follicular proliferation and increased
apoptosis
To test whether, besides being required, TGF-ß1 by itself
is sufficient to induce catagen in vivo, back skin of
adolescent C57BL/6 mice with all hair follicles in synchronized,
depilation-induced anagen VI was treated for 3 days with a high dose of
TGF-ß1 s.c. (2 µg total). Quantitative histomorphometry at day 18
after depilation revealed that HF in control back skin were still in
late anagen VI (Fig. 5A
, Fig. 6
). In contrast, TGF-ß1 injection resulted in premature catagen
development, which was limited to the site of injection. In this area,
HF had entered already different stages of anagen-catagen
transformation, ranging from anagen VI to catagen VI (Fig. 5B
, Fig. 6
).
|
Two of the five test mice (but none of the control mice)
displayed areas of dermal fibrosis (not shown), and one to three HF per
injection site were found to show typical characteristics of HF
dystrophy (3
, 34
, 40)
, such as single ectopic melanin
granules and larger clumps of ectopic melanin (Fig. 5C
).
Induction of catagen development was dose dependent. Lower doses of
TGF-ß1 (0.5 µg, 0.2 µg) showed also an induction of hair follicle
regression, but to a lesser extent (data not shown), and no dermal
fibrosis or ectopic melanin granules were detectable. Outside of the
injection area, HF were still in anagen VI, as in control animals
injected with vehicle alone.
Quantitative histomorphometry of TUNEL+ cells revealed a 2.5-fold
increase of TUNEL+ fragments in anagen VI to catagen II HF after
repetitive TGF-ß1 injection compared to the vehicle-treated control
skin (Fig. 2f, g
, Fig. 7
). Apoptotic nuclei were found mainly in the hair bulb and keratinocytes
of the ORS.
|
Thus, high-dose TGF-ß1 is able to induce localized, premature catagen
development accompanied by increased apoptosis in follicular
keratinocytes in vivo. This is in line with previous
in vitro reports on rat and human HF (14)
. In
addition, injection of TGF-ß1 occasionally induced fibrosis and mild
hair follicle dystrophy at the site of injection. Reversible induction
of fibrosis by TGF-ß1 at the site of injection and induction of
angiogenesis have been described already earlier (41)
.
Like fibrosis, the induction of catagen was also restricted to the
injection site. Since components of the extracellular matrix are major
regulatory elements for TGF-ß activity in situ (42
, 43)
, the localized effects of TGF-ß1 may be explained by
cytokine binding to the extracellular matrix, which may serve to
inactivate TGF-ß proteins with increasing distance from the site of
injection.
This study shows that TGF-ß1 is indeed involved in the regulation of
hair follicle regression and is by itself able to induce premature
catagen in vivo by induction of apoptosis and inhibition of
keratinocyte proliferation (8
, 13
14
15)
. However, the
delay, but not complete block, of hair follicles to enter catagen
suggests that other factors also participate to control catagen
development (44)
.
Given the crucial role of catagen control for most hair disorders seen
in humans (alopecia, effluvium, hirsutism) (5
, 44
, 45)
,
this has important clinical implications. Our data strongly encourage
one to systematically explore to what extent synthetic (ideally,
topically administered) TGF-ß receptor II agonists and antagonists
can be used in the management of human hair growth disorders in order
to induce premature catagen development (e.g., for the management of
hirsutism) or to inhibit it as a novel strategy for the management of
various forms of alopecia and effluvium.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96,319-328[Medline]
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D. J. Tobin, K. Foitzik, T. Reinheckel, L. Mecklenburg, V. A. Botchkarev, C. Peters, and R. Paus The Lysosomal Protease Cathepsin L Is an Important Regulator of Keratinocyte and Melanocyte Differentiation During Hair Follicle Morphogenesis and Cycling Am. J. Pathol., May 1, 2002; 160(5): 1807 - 1821. [Abstract] [Full Text] [PDF]
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B. Li, D. R. Mackay, Q. Dai, T. W. H. Li, M. Nair, M. Fallahi, C. P. Schonbaum, J. Fantes, A. P. Mahowald, M. L. Waterman, et al. The LEF1/beta -catenin complex activates movo1, a mouse homolog of Drosophila ovo required for epidermal appendage differentiation PNAS, April 30, 2002; 99(9): 6064 - 6069. [Abstract] [Full Text] [PDF]
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X. Liu, V. Alexander, K. Vijayachandra, E. Bhogte, I. Diamond, and A. Glick Conditional epidermal expression of TGFbeta 1 blocks neonatal lethality but causes a reversible hyperplasia and alopecia PNAS, July 31, 2001; 98(16): 9139 - 9144. [Abstract] [Full Text] [PDF]
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V. A. Botchkarev, E. A. Komarova, F. Siebenhaar, N. V. Botchkareva, A. A. Sharov, P. G. Komarov, M. Maurer, A. V. Gudkov, and B. A. Gilchrest p53 Involvement in the Control of Murine Hair Follicle Regression Am. J. Pathol., June 1, 2001; 158(6): 1913 - 1919. [Abstract] [Full Text] [PDF]
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 V. A. BOTCHKAREV, N. V. BOTCHKAREVA, K. M. ALBERS, L.-H. CHEN, P. WELKER, and R. PAUS A role for p75 neurotrophin receptor in the control of apoptosis-driven hair follicle regression FASEB J, October 1, 2000; 14(13): 1931 - 1942. [Abstract] [Full Text]
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