Towards dissecting the pathogenesis of retinoid-induced hair loss: All-trans retinoic acid induces premature hair follicle regression (catagen) by upregulation of transforming growth factor-β2 in the dermal papilla

Kerstin Foitzik, Tanja Spexard, Motonobu Nakamura, Ursula Halsner, Ralf Paus

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Diffuse hair loss ranks among the most frequent and psychologically most distressing adverse effects of systemic therapy with retinoids, which severely limits their therapeutic use even where clinically desired. Since the underlying mechanisms of retinoid-induced effluvium are as yet unknown, we have investigated the influence of the prototypic retinoid all-trans retinoic acid (ATRA, tretinoin) on the growth of human scalp hair follicles (HF) in culture. HF in the anagen VI stage of the hair cycle were cultured in the presence of 10-8 or 10-10 M ATRA. Compared with controls, hair shaft elongation declined significantly already after 2 d in the ATRA-treated group, and approximately 80% of the ATRA-treated HF had prematurely entered catagen-like stage at day 6, compared with 30% in the control group. This corresponded to an upregulation of apoptotic and a downregulation of Ki67-positive cells in ATRA-treated HF. Since transforming growth factor (TGF)-β has been implicated as a key inducer of catagen, we next studied whether ATRA treatment had any effect on follicular expression. TGF-β2 immunoreactivity was detected in the outer root sheath of anagen VI scalp HF. In catagen follicles, TGF-β2 was also expressed in the regressing epithelial strand. After 4 d of ATRA treatment, TGF-β2 was significantly upregulated in anagen HF in the dermal papilla (DP) and the dermal sheath, 7, and TGF-β neutralizing antibody partially abrogated at RA induced hair growth inhibition. Real-time PCR confirmed a significant upregulation of TGF-β2 transcripts in ATRA-treated hair bulbs. This study is the first to provide direct evidence that ATRA can indeed induce a catagen-like stage in human HF and suggests that this occurs, at least in part, via upregulation of TGF-β2 in the DP. Therefore, topical TGF-β2/TGF-β receptor II antagonists deserve to be explored for the prevention and management of retinoid-induced hair loss.

Original languageEnglish (US)
Pages (from-to)1119-1126
Number of pages8
JournalJournal of Investigative Dermatology
Volume124
Issue number6
DOIs
StatePublished - Jan 1 2005
Externally publishedYes

Fingerprint

Hair Follicle
Alopecia
Retinoids
Transforming Growth Factors
Tretinoin
Up-Regulation
Skin
Hair
Scalp
Growth Factor Receptors
Therapeutic Uses
Growth
Neutralizing Antibodies
Real-Time Polymerase Chain Reaction
Elongation
Down-Regulation
Cells
Control Groups

Keywords

  • Anagen
  • Catagen
  • Effluvium
  • Retinoic acid
  • Telogen
  • Tretinoin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

Cite this

@article{8caf181ecafe40918f282334f6a2956b,
title = "Towards dissecting the pathogenesis of retinoid-induced hair loss: All-trans retinoic acid induces premature hair follicle regression (catagen) by upregulation of transforming growth factor-β2 in the dermal papilla",
abstract = "Diffuse hair loss ranks among the most frequent and psychologically most distressing adverse effects of systemic therapy with retinoids, which severely limits their therapeutic use even where clinically desired. Since the underlying mechanisms of retinoid-induced effluvium are as yet unknown, we have investigated the influence of the prototypic retinoid all-trans retinoic acid (ATRA, tretinoin) on the growth of human scalp hair follicles (HF) in culture. HF in the anagen VI stage of the hair cycle were cultured in the presence of 10-8 or 10-10 M ATRA. Compared with controls, hair shaft elongation declined significantly already after 2 d in the ATRA-treated group, and approximately 80{\%} of the ATRA-treated HF had prematurely entered catagen-like stage at day 6, compared with 30{\%} in the control group. This corresponded to an upregulation of apoptotic and a downregulation of Ki67-positive cells in ATRA-treated HF. Since transforming growth factor (TGF)-β has been implicated as a key inducer of catagen, we next studied whether ATRA treatment had any effect on follicular expression. TGF-β2 immunoreactivity was detected in the outer root sheath of anagen VI scalp HF. In catagen follicles, TGF-β2 was also expressed in the regressing epithelial strand. After 4 d of ATRA treatment, TGF-β2 was significantly upregulated in anagen HF in the dermal papilla (DP) and the dermal sheath, 7, and TGF-β neutralizing antibody partially abrogated at RA induced hair growth inhibition. Real-time PCR confirmed a significant upregulation of TGF-β2 transcripts in ATRA-treated hair bulbs. This study is the first to provide direct evidence that ATRA can indeed induce a catagen-like stage in human HF and suggests that this occurs, at least in part, via upregulation of TGF-β2 in the DP. Therefore, topical TGF-β2/TGF-β receptor II antagonists deserve to be explored for the prevention and management of retinoid-induced hair loss.",
keywords = "Anagen, Catagen, Effluvium, Retinoic acid, Telogen, Tretinoin",
author = "Kerstin Foitzik and Tanja Spexard and Motonobu Nakamura and Ursula Halsner and Ralf Paus",
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T2 - All-trans retinoic acid induces premature hair follicle regression (catagen) by upregulation of transforming growth factor-β2 in the dermal papilla

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AU - Spexard, Tanja

AU - Nakamura, Motonobu

AU - Halsner, Ursula

AU - Paus, Ralf

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N2 - Diffuse hair loss ranks among the most frequent and psychologically most distressing adverse effects of systemic therapy with retinoids, which severely limits their therapeutic use even where clinically desired. Since the underlying mechanisms of retinoid-induced effluvium are as yet unknown, we have investigated the influence of the prototypic retinoid all-trans retinoic acid (ATRA, tretinoin) on the growth of human scalp hair follicles (HF) in culture. HF in the anagen VI stage of the hair cycle were cultured in the presence of 10-8 or 10-10 M ATRA. Compared with controls, hair shaft elongation declined significantly already after 2 d in the ATRA-treated group, and approximately 80% of the ATRA-treated HF had prematurely entered catagen-like stage at day 6, compared with 30% in the control group. This corresponded to an upregulation of apoptotic and a downregulation of Ki67-positive cells in ATRA-treated HF. Since transforming growth factor (TGF)-β has been implicated as a key inducer of catagen, we next studied whether ATRA treatment had any effect on follicular expression. TGF-β2 immunoreactivity was detected in the outer root sheath of anagen VI scalp HF. In catagen follicles, TGF-β2 was also expressed in the regressing epithelial strand. After 4 d of ATRA treatment, TGF-β2 was significantly upregulated in anagen HF in the dermal papilla (DP) and the dermal sheath, 7, and TGF-β neutralizing antibody partially abrogated at RA induced hair growth inhibition. Real-time PCR confirmed a significant upregulation of TGF-β2 transcripts in ATRA-treated hair bulbs. This study is the first to provide direct evidence that ATRA can indeed induce a catagen-like stage in human HF and suggests that this occurs, at least in part, via upregulation of TGF-β2 in the DP. Therefore, topical TGF-β2/TGF-β receptor II antagonists deserve to be explored for the prevention and management of retinoid-induced hair loss.

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