hedgehog_info
Member
- Reaction score
- 0
looks like the program got pushed back by a little
Abstract:
The hedgehog (Hh) family of intercellular signaling proteins is intricately linked to the development and patterning
of almost every major vertebrate organ system. In the skin, sonic hedgehog (Shh) is required for hair follicle
morphogenesis during embryogenesis and for regulating follicular growth and cycling in the adult. We recently
described the identification and characterization of synthetic, non-peptidyl small molecule agonists of the Hh
pathway. In this study, we examined the ability of a topically applied Hh-agonist to modulate follicular cycling in
adult mouse skin. We report that the Hh-agonist can stimulate the transition from the resting (telogen) to the growth
(anagen) stage of the hair cycle in adult mouse skin. Hh-agonist-induced hair growth caused no detectable differences
in epidermal proliferation, differentiation, or in the endogenous Hh-signaling pathway as measured by
Gli1, Shh, Ptc1, and Gli2 gene expression when compared with a normal hair cycle. In addition, we demonstrate that
Hh-agonist is active in human scalp in vitro as measured by Gli1 gene expression. These results suggest that the
topical application of Hh-agonist could be effective in treating conditions of decreased proliferation and aberrant
follicular cycling in the scalp including androgenetic alopecia (pattern hair loss).
A few snippets:
By day 18–19, both Hh-agonist and depilated skin had
entered into catagen (Fig 2Q, R) and by day 23 had completed
the hair cycle and the follicles were once again in
telogen (Fig 2S, T).
Since it is well established that aberrant Hh pathway activity
in skin can lead to abnormal differentiation and various
follicular hyperplasias including BCC (Hahn et al, 1996;
Johnson et al, 1996; Dahmane et al, 1997; Oro et al, 1997;
Xie et al, 1998; Aszterbaum et al, 1999; Grachtchouk et al,
2000; Nilsson et al, 2000; Sheng et al, 2002), the effect of
Hh-agonist on differentiation in the skin was analyzed.
Seven-wk-old C57BL/6 male mice were either treated with
one topical dose of vehicle, Hh-agonist, or depilated to induce
anagen. Although hair follicles from vehicle-treated
skin were still in telogen 10 d after treatment (Fig 4A) both
depilated (Fig 4F) and Hh-agonist-treated hair follicles
(Fig 4K) were in anagen VI of the hair cycle. At this substage
of anagen, hair follicle size, proliferation, and hair
production are at their maximum.
The long-term effects of Hh-agonist treatment on proliferation
and differentiation in mouse skin were also examined.
Seven-wk-old mice were treated with either one
topical dose of vehicle or Hh-agonist to induce anagen.
Approximately 1 y later, skin from both groups was analyzed
by light microscopy and immunohistochemistry. Hair follicles
from both vehicle (Fig 5A)- and Hh-agonist (Fig 5B)-
treated skin were in telogen.
We have reproduced a defined biological role of Shh in the
adult mouse, namely the ability to modulate hair growth and
follicular cycling, by the topical application of a small molecule
agonist of the Hh-signaling pathway. This work further
validates the concept that Hh-signaling in the adult vertebrate
can be modulated in order to achieve a desired biological
effect. One application of the Hh-agonist was able
to induce anagen in adult C57BL/6 mice. The resultant hair
cycle was indistinguishable from a normal hair cycle (depilation
model) with no detectable differences in the cycle
length, histology, expression of Hh-pathway genes, epidermal
proliferation, differentiation, melanogenesis, or, ultimately,
in the hair produced. In addition, Hh-agonist
treatment did not appear to have any long-term effects on
the skin. Furthermore, we have also demonstrated that the
Hh-agonist is active in human scalp as measured by the
induction of Hh-pathway gene expression.
In the case of anagen induction,
a small amount is enough to trigger hair growth that
occurs without causing any detectable differences when
compared with a normal hair cycle. Collectively, these
properties of the Hh-agonist class of compounds make
them suitable candidates for potential therapeutic indications
that require topical application.
Since scalp affected with pattern hair loss has a higher
percentage of hair follicles in telogen, the ability of Hh-agonist
to promote anagen suggests that it may be useful as a
potential therapeutic agent. The Hh-agonist may also enhance
follicular proliferation and the size, proliferation, and/
or organization of the dermal papillae in hair follicles affected
by pattern hair loss. Ultimately, this potential combination
of increasing the percentage of follicles in anagen and
helping to restore a more normal follicular architecture may
have a positive effect on hair growth. We have shown that
the Hh-agonist is able to activate the Hh pathway in human
scalp (Fig 6). Preliminary experiments suggest that adult
scalp, and in particular, alopecic scalp, is also responsive to
Hh-agonist as measured by Gli1 induction (data not shown).
Although these data are compelling, the physiological response
to Hh-pathway activation in normal and human
scalp affected with pattern hair loss needs to be determined
in an in vivo context. In conclusion, we propose that the use
of small molecule agonists of the Hh pathway may be a
potential therapeutic agent in the treatment of male and
female pattern hair loss.
Paladini RD, Saleh J, Qian C, Xu GX, Rubin LL.
Modulation of hair growth with small molecule agonists of the hedgehog signaling pathway.
J Invest Dermatol. 2005 Oct;125(4):638-46.
PMID: 16185261 [PubMed - indexed for MEDLINE]
___________________________________________________________
Abstract:
The hedgehog (Hh) family of intercellular signaling proteins is intricately linked to the development and patterning
of almost every major vertebrate organ system. In the skin, sonic hedgehog (Shh) is required for hair follicle
morphogenesis during embryogenesis and for regulating follicular growth and cycling in the adult. We recently
described the identification and characterization of synthetic, non-peptidyl small molecule agonists of the Hh
pathway. In this study, we examined the ability of a topically applied Hh-agonist to modulate follicular cycling in
adult mouse skin. We report that the Hh-agonist can stimulate the transition from the resting (telogen) to the growth
(anagen) stage of the hair cycle in adult mouse skin. Hh-agonist-induced hair growth caused no detectable differences
in epidermal proliferation, differentiation, or in the endogenous Hh-signaling pathway as measured by
Gli1, Shh, Ptc1, and Gli2 gene expression when compared with a normal hair cycle. In addition, we demonstrate that
Hh-agonist is active in human scalp in vitro as measured by Gli1 gene expression. These results suggest that the
topical application of Hh-agonist could be effective in treating conditions of decreased proliferation and aberrant
follicular cycling in the scalp including androgenetic alopecia (pattern hair loss).
A few snippets:
By day 18–19, both Hh-agonist and depilated skin had
entered into catagen (Fig 2Q, R) and by day 23 had completed
the hair cycle and the follicles were once again in
telogen (Fig 2S, T).
Since it is well established that aberrant Hh pathway activity
in skin can lead to abnormal differentiation and various
follicular hyperplasias including BCC (Hahn et al, 1996;
Johnson et al, 1996; Dahmane et al, 1997; Oro et al, 1997;
Xie et al, 1998; Aszterbaum et al, 1999; Grachtchouk et al,
2000; Nilsson et al, 2000; Sheng et al, 2002), the effect of
Hh-agonist on differentiation in the skin was analyzed.
Seven-wk-old C57BL/6 male mice were either treated with
one topical dose of vehicle, Hh-agonist, or depilated to induce
anagen. Although hair follicles from vehicle-treated
skin were still in telogen 10 d after treatment (Fig 4A) both
depilated (Fig 4F) and Hh-agonist-treated hair follicles
(Fig 4K) were in anagen VI of the hair cycle. At this substage
of anagen, hair follicle size, proliferation, and hair
production are at their maximum.
The long-term effects of Hh-agonist treatment on proliferation
and differentiation in mouse skin were also examined.
Seven-wk-old mice were treated with either one
topical dose of vehicle or Hh-agonist to induce anagen.
Approximately 1 y later, skin from both groups was analyzed
by light microscopy and immunohistochemistry. Hair follicles
from both vehicle (Fig 5A)- and Hh-agonist (Fig 5B)-
treated skin were in telogen.
We have reproduced a defined biological role of Shh in the
adult mouse, namely the ability to modulate hair growth and
follicular cycling, by the topical application of a small molecule
agonist of the Hh-signaling pathway. This work further
validates the concept that Hh-signaling in the adult vertebrate
can be modulated in order to achieve a desired biological
effect. One application of the Hh-agonist was able
to induce anagen in adult C57BL/6 mice. The resultant hair
cycle was indistinguishable from a normal hair cycle (depilation
model) with no detectable differences in the cycle
length, histology, expression of Hh-pathway genes, epidermal
proliferation, differentiation, melanogenesis, or, ultimately,
in the hair produced. In addition, Hh-agonist
treatment did not appear to have any long-term effects on
the skin. Furthermore, we have also demonstrated that the
Hh-agonist is active in human scalp as measured by the
induction of Hh-pathway gene expression.
In the case of anagen induction,
a small amount is enough to trigger hair growth that
occurs without causing any detectable differences when
compared with a normal hair cycle. Collectively, these
properties of the Hh-agonist class of compounds make
them suitable candidates for potential therapeutic indications
that require topical application.
Since scalp affected with pattern hair loss has a higher
percentage of hair follicles in telogen, the ability of Hh-agonist
to promote anagen suggests that it may be useful as a
potential therapeutic agent. The Hh-agonist may also enhance
follicular proliferation and the size, proliferation, and/
or organization of the dermal papillae in hair follicles affected
by pattern hair loss. Ultimately, this potential combination
of increasing the percentage of follicles in anagen and
helping to restore a more normal follicular architecture may
have a positive effect on hair growth. We have shown that
the Hh-agonist is able to activate the Hh pathway in human
scalp (Fig 6). Preliminary experiments suggest that adult
scalp, and in particular, alopecic scalp, is also responsive to
Hh-agonist as measured by Gli1 induction (data not shown).
Although these data are compelling, the physiological response
to Hh-pathway activation in normal and human
scalp affected with pattern hair loss needs to be determined
in an in vivo context. In conclusion, we propose that the use
of small molecule agonists of the Hh pathway may be a
potential therapeutic agent in the treatment of male and
female pattern hair loss.
Paladini RD, Saleh J, Qian C, Xu GX, Rubin LL.
Modulation of hair growth with small molecule agonists of the hedgehog signaling pathway.
J Invest Dermatol. 2005 Oct;125(4):638-46.
PMID: 16185261 [PubMed - indexed for MEDLINE]