DOI: 10.1111/exd.12471 www.wileyonlinelibrary.com/journal/EXD
Commentary from the Editorial Board
A newly discovered linkage between proteoglycans and hair biology: decorin acts as an anagen inducer Shigeki Inui and Satoshi Itami Department of Regenerative Dermatology, Osaka University Graduate School of Medicine, Suita, Japan Correspondence: Satoshi Itami, Department of Regenerative Dermatology, Osaka University Graduate School of Medicine, 2-2, G2, Yamadaoka, Suita-shi, Osaka 5650871, Japan, Tel.: +81-6-6879-3960, Fax: +81-6-6879-3962, e-mail: [email protected] Abstract: Proteoglycans have been suggested to play pivotal roles in hair biology. Decorin is a prototypical member of the small leucine-rich proteoglycan family, which is involved in numerous biological processes. However, the role of decorin in the hair cycle has not been elucidated. Moreover, the effects of decorin on the activities of many growth factors are complex, and it is hard to predict whether decorin would affect hair growth or the hair cycle positively or negatively. Jing et al. focused on the potential role of decorin in the hair cycle and found that decorin is highly expressed in the epidermis, in hair follicle epithelial cells and in dermal papilla cells in the anagen phase. The expression of
It is well known that the expression of versican, a representative proteoglycan in the skin, can maintain the hair induction ability of dermal papilla cells (1). Therefore, proteoglycans have been suggested to play pivotal roles in hair biology. In this issue of Experimental Dermatology, a Chinese research group reports the potential role of decorin, a well-known proteoglycan, in hair cycling and they identify it as a new anagen inducer (2). Their study demonstrates a new linkage between proteoglycans and hair biology. Decorin is a prototypical member of the small leucine-rich proteoglycan gene family, which consists of a glycosaminoglycan and protein core with 12 leucine-rich repeats. Decorin regulates collagen fibrillogenesis (3) and blocks TGF-b1 activity (4) via direct interactions with collagens and TGF-b1, respectively. The crosstalk between TGF-b1 and decorin is referred to as the decorin-TGF-b axis (5). Additionally, decorin directly antagonizes the receptor tyrosine kinase family, including the EGF receptor (6), the type I IGF receptor (7) and the HGF receptor (Met) (8). The ligands of those receptors reportedly regulate hair cycling (9–11), suggesting the potential role of decorin in the hair cycle. Indeed, decorin was previously reported to be expressed in the dermal papilla extracellular matrix (12) and was also identified as one of the up-regulated genes in the human anagen hair follicle bulge in a study searching for new hair bulge markers (13). These findings suggest the potential role of decorin in hair follicle development and cycling. As mentioned above, the effects of decorin on the activities of many growth factors are complex (Table 1) and therefore it is hard to predict whether decorin would affect the hair cycle positively or negatively. The paper by Jing et al.(2) in this issue clarifies that decorin is highly expressed in hair follicles of anagen, accelerates anagen and delays catagen transition as a positive regulator in the hair cycle. First, their immunohistochemical
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2014, 23, 547–548
decorin was decreased during catagen to telogen, except for the bulge region. Exogenous administration of decorin accelerated anagen and delayed catagen transition as a positive regulator of the hair cycle. Because TGF-b is one of the androgen-induced pathogenic factors in androgenetic alopecia, this study provides clues to understand the pathogenesis and new therapeutic targets of hair loss. Key words: decorin – growth factor – hair cycle
Accepted for publication 11 June 2014
Table 1. Hair cycle regulators inhibited by decorin Hair cycle regulator
Function in hair cycle
Reference
TGF-b IGF-I Met (HGF receptor) EGFR
Catagen inducer Anagen maintainer Anagen inducer and mainainer Catagen inducer
Foitzik et al. (15) Philpott et al. (10) Jindo et al. (11) Murillas et al. (9)
study reveals that decorin is intensely expressed throughout the interfollicular epidermis and is moderately expressed in the dermal papilla and in sebaceous gland cells during the early anagen phase (anagen II) of murine dorsal skin. During anagen IV, decorin is moderately expressed in the epidermis, in the outer and inner root sheaths and in the cortex. In particular, decorin is significantly expressed in the isthmus proximal to the bulge at this stage. In the catagen phase, decorin expression is reduced and, in telogen, only weak expression is observed. This regulation of decorin during various hair cycle phases was confirmed by Western blot and RT-PCR using murine dorsal skin samples at the protein and mRNA levels, respectively. Moreover, the authors investigated the effects of recombinant human decorin (rh-decorin) injected into murine skin using the synchronized hair cycle model and found that it accelerates anagen onset and delays catagen transition, thereby prolonging the anagen phase. These findings were evidenced by observations of hair shaft length, follicular bulbar diameter, hair follicle cycling score and follicular phase percentage. Collectively, they show that decorin acts as an anagen inducer in the hair cycle. This finding supports the recent postulation that the competition between morphogens and extracellular matrix secretion in the dermal papilla regulates the transition from neogen (morphogenesis phase) to anagen (14).
547
Commentary from the Editorial Board
As the catagen delay observed in mice injected with rh-decorin was similar to that in TGF-b null mice (15), the authors hypothesized that the effect of decorin on the hair cycle is mediated through its effect on TGF-b signalling. This notion is interesting because TGF-b has been considered as one of the androgeninduced pathogenic factors in androgenetic alopecia (16–19). On the other hand, it has very recently been reported that the downregulation of IGF-I from the dermal papilla is an important pathological mechanism of androgenetic alopecia (20). The fact that decorin antagonizes the type I IGF receptor (7) then appears to be paradoxical in the pathogenesis of androgenetic alopecia. Likewise, decorin antagonizes the HGF receptor (8), which when activated by its ligand HGF, accelerates anagen transition and delays catagen transition (11), providing another paradox. However, decorin suppresses androgen receptor signalling by inhibiting its phosphorylation in human prostate cancer cells (21), indicating the possibility that decorin can affect androgenetic alopecia by modulating androgen receptor signalling pathways. EGFR signalling is required for punctual catagen transition (9) and plays an important role in chemotherapy-induced alopecia, which has been recently shown by the resistance of Egfr mutant mice to chemotherapy-induced alopecia (22). Therefore, the suppression of EGFR by decorin can be a potential therapeutic pathway for chemotherapy-induced alopecia. While Jing et al. focused on hair cycling (2), decorin may also be involved in hair follicle development because very recently it has been reported that decorin promotes the aggregation of
References
1 Kishimoto J, Ehama R, Wu L et al. Proc Natl Acad Sci U S A 1999: 96: 7336–7341. 2 Jing J, Wu X J, Li YL, Cai S Q, Zheng M, Lu Z F. Exp Dermatol 2014: 23: 486–491. 3 Weber I T, Harrison R W, Iozzo R V. J Biol Chem 1996: 271: 31767–31770. 4 Yamaguchi Y, Mann D M, Ruoslahti E. Nature 1990: 346: 281–284. 5 Baghy K, Iozzo R V, Kovalszky I. J Histochem Cytochem 2012: 60: 262–268. 6 Csordas G, Santra M, Reed C C et al. J Biol Chem 2000: 275: 32879–32887. 7 Schonherr E, Sunderkotter C, Iozzo R V et al. J Biol Chem 2005: 280: 15767–15772. 8 Goldoni S, Humphries A, Nystrom A et al. J Cell Biol 2009: 185: 743–754.
548
undifferentiated mesenchymal precursor cells during limb development (23). This discovery suggests that decorin may play a role in dermal condensation during hair follicle development. The staining pattern of decorin shown by the authors was mainly cytoplasmic in the epidermis and in the hair follicle epithelium. Further, another group reported that decorin is detected in total cell extracts from cultured human keratinocytes but not in extracellular matrix extracts (24), which indicates that keratinocytes are unable to secrete decorin. However, the physiological function(s) of intra-cytoplasmic decorin was not clarified in that study. The authors injected rh-decorin into mouse skin and found that it induces anagen onset and catagen delay. Collectively, decorin, which is secreted from cells other than epidermal and hair follicle keratinocytes, might affect the hair cycle. Conditional deletion of the decorin gene in follicular keratinocytes will provide a deeper insight into the effect of decorin in hair follicles and will provide more profound insights of hair biology. Together, in the near future, we expect new progress to solve two critical questions; (i) from the basic aspect, from which component of the skin is the decorin that functions in anagen induction derived?; and (ii) from the clinical aspect, as the injection of decorin works well in murine experiments, can we clinically utilize it for hair loss diseases in humans?
Acknowledgements S Inui and S Itami wrote this manuscript.
Conflict of interests The authors have declared no conflicting interests.
9 Murillas R, Larcher F, Conti C J et al. EMBO J 1995: 14: 5216–5223. 10 Philpott M P, Sanders D A, Kealey T. J Invest Dermatol 1994: 102: 857–861. 11 Jindo T, Tsuboi R, Takamori K et al. J Invest Dermatol 1998: 110: 338–342. 12 Couchman J R. J Invest Dermatol 1993: 101: 60S–64S. 13 Ohyama M, Terunuma A, Tock C L et al. J Clin Invest 2006: 116: 249–260. 14 Bernard B A. Exp Dermatol 2012: 21: 401–403. 15 Foitzik K, Lindner G, Mueller-Roever S et al. FASEB J 2000: 14: 752–760. 16 Inui S, Fukuzato Y, Nakajima T et al. FASEB J 2002: 16: 1967–1969. 17 Yoo H G, Kim J S, Lee S R et al. Biol Pharm Bull 2006: 29: 1246–1250.
18 Inui S, Itami S. Exp Dermatol 2013: 22: 168–171. 19 Shin H, Yoo H G, Inui S et al. BMB Rep 2013: 46: 460–464. 20 Panchaprateep R, Asawanonda P. Exp Dermatol 2014: 23: 216–218. 21 Hu Y, Sun H, Owens R T et al. Neoplasia 2009: 11: 1042–1053. 22 Bichsel K J, Gogia N, Malouff T et al. PLoS ONE 2013: 8: e69368. 23 Lorda-Diez C I, Garcia-Porrero J A, Hurle J M et al. Gene Expr Patterns 2014: 15: 52–60. 24 Velez-DelValle C, Marsch-Moreno M, CastroMunozledo F et al. Biochem Biophys Res Commun 2011: 411: 168–174.
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2014, 23, 547–548
Commentary from the Editorial Board
A newly discovered linkage between proteoglycans and hair biology: decorin acts as an anagen inducer Shigeki Inui and Satoshi Itami Department of Regenerative Dermatology, Osaka University Graduate School of Medicine, Suita, Japan Correspondence: Satoshi Itami, Department of Regenerative Dermatology, Osaka University Graduate School of Medicine, 2-2, G2, Yamadaoka, Suita-shi, Osaka 5650871, Japan, Tel.: +81-6-6879-3960, Fax: +81-6-6879-3962, e-mail: [email protected] Abstract: Proteoglycans have been suggested to play pivotal roles in hair biology. Decorin is a prototypical member of the small leucine-rich proteoglycan family, which is involved in numerous biological processes. However, the role of decorin in the hair cycle has not been elucidated. Moreover, the effects of decorin on the activities of many growth factors are complex, and it is hard to predict whether decorin would affect hair growth or the hair cycle positively or negatively. Jing et al. focused on the potential role of decorin in the hair cycle and found that decorin is highly expressed in the epidermis, in hair follicle epithelial cells and in dermal papilla cells in the anagen phase. The expression of
It is well known that the expression of versican, a representative proteoglycan in the skin, can maintain the hair induction ability of dermal papilla cells (1). Therefore, proteoglycans have been suggested to play pivotal roles in hair biology. In this issue of Experimental Dermatology, a Chinese research group reports the potential role of decorin, a well-known proteoglycan, in hair cycling and they identify it as a new anagen inducer (2). Their study demonstrates a new linkage between proteoglycans and hair biology. Decorin is a prototypical member of the small leucine-rich proteoglycan gene family, which consists of a glycosaminoglycan and protein core with 12 leucine-rich repeats. Decorin regulates collagen fibrillogenesis (3) and blocks TGF-b1 activity (4) via direct interactions with collagens and TGF-b1, respectively. The crosstalk between TGF-b1 and decorin is referred to as the decorin-TGF-b axis (5). Additionally, decorin directly antagonizes the receptor tyrosine kinase family, including the EGF receptor (6), the type I IGF receptor (7) and the HGF receptor (Met) (8). The ligands of those receptors reportedly regulate hair cycling (9–11), suggesting the potential role of decorin in the hair cycle. Indeed, decorin was previously reported to be expressed in the dermal papilla extracellular matrix (12) and was also identified as one of the up-regulated genes in the human anagen hair follicle bulge in a study searching for new hair bulge markers (13). These findings suggest the potential role of decorin in hair follicle development and cycling. As mentioned above, the effects of decorin on the activities of many growth factors are complex (Table 1) and therefore it is hard to predict whether decorin would affect the hair cycle positively or negatively. The paper by Jing et al.(2) in this issue clarifies that decorin is highly expressed in hair follicles of anagen, accelerates anagen and delays catagen transition as a positive regulator in the hair cycle. First, their immunohistochemical
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2014, 23, 547–548
decorin was decreased during catagen to telogen, except for the bulge region. Exogenous administration of decorin accelerated anagen and delayed catagen transition as a positive regulator of the hair cycle. Because TGF-b is one of the androgen-induced pathogenic factors in androgenetic alopecia, this study provides clues to understand the pathogenesis and new therapeutic targets of hair loss. Key words: decorin – growth factor – hair cycle
Accepted for publication 11 June 2014
Table 1. Hair cycle regulators inhibited by decorin Hair cycle regulator
Function in hair cycle
Reference
TGF-b IGF-I Met (HGF receptor) EGFR
Catagen inducer Anagen maintainer Anagen inducer and mainainer Catagen inducer
Foitzik et al. (15) Philpott et al. (10) Jindo et al. (11) Murillas et al. (9)
study reveals that decorin is intensely expressed throughout the interfollicular epidermis and is moderately expressed in the dermal papilla and in sebaceous gland cells during the early anagen phase (anagen II) of murine dorsal skin. During anagen IV, decorin is moderately expressed in the epidermis, in the outer and inner root sheaths and in the cortex. In particular, decorin is significantly expressed in the isthmus proximal to the bulge at this stage. In the catagen phase, decorin expression is reduced and, in telogen, only weak expression is observed. This regulation of decorin during various hair cycle phases was confirmed by Western blot and RT-PCR using murine dorsal skin samples at the protein and mRNA levels, respectively. Moreover, the authors investigated the effects of recombinant human decorin (rh-decorin) injected into murine skin using the synchronized hair cycle model and found that it accelerates anagen onset and delays catagen transition, thereby prolonging the anagen phase. These findings were evidenced by observations of hair shaft length, follicular bulbar diameter, hair follicle cycling score and follicular phase percentage. Collectively, they show that decorin acts as an anagen inducer in the hair cycle. This finding supports the recent postulation that the competition between morphogens and extracellular matrix secretion in the dermal papilla regulates the transition from neogen (morphogenesis phase) to anagen (14).
547
Commentary from the Editorial Board
As the catagen delay observed in mice injected with rh-decorin was similar to that in TGF-b null mice (15), the authors hypothesized that the effect of decorin on the hair cycle is mediated through its effect on TGF-b signalling. This notion is interesting because TGF-b has been considered as one of the androgeninduced pathogenic factors in androgenetic alopecia (16–19). On the other hand, it has very recently been reported that the downregulation of IGF-I from the dermal papilla is an important pathological mechanism of androgenetic alopecia (20). The fact that decorin antagonizes the type I IGF receptor (7) then appears to be paradoxical in the pathogenesis of androgenetic alopecia. Likewise, decorin antagonizes the HGF receptor (8), which when activated by its ligand HGF, accelerates anagen transition and delays catagen transition (11), providing another paradox. However, decorin suppresses androgen receptor signalling by inhibiting its phosphorylation in human prostate cancer cells (21), indicating the possibility that decorin can affect androgenetic alopecia by modulating androgen receptor signalling pathways. EGFR signalling is required for punctual catagen transition (9) and plays an important role in chemotherapy-induced alopecia, which has been recently shown by the resistance of Egfr mutant mice to chemotherapy-induced alopecia (22). Therefore, the suppression of EGFR by decorin can be a potential therapeutic pathway for chemotherapy-induced alopecia. While Jing et al. focused on hair cycling (2), decorin may also be involved in hair follicle development because very recently it has been reported that decorin promotes the aggregation of
References
1 Kishimoto J, Ehama R, Wu L et al. Proc Natl Acad Sci U S A 1999: 96: 7336–7341. 2 Jing J, Wu X J, Li YL, Cai S Q, Zheng M, Lu Z F. Exp Dermatol 2014: 23: 486–491. 3 Weber I T, Harrison R W, Iozzo R V. J Biol Chem 1996: 271: 31767–31770. 4 Yamaguchi Y, Mann D M, Ruoslahti E. Nature 1990: 346: 281–284. 5 Baghy K, Iozzo R V, Kovalszky I. J Histochem Cytochem 2012: 60: 262–268. 6 Csordas G, Santra M, Reed C C et al. J Biol Chem 2000: 275: 32879–32887. 7 Schonherr E, Sunderkotter C, Iozzo R V et al. J Biol Chem 2005: 280: 15767–15772. 8 Goldoni S, Humphries A, Nystrom A et al. J Cell Biol 2009: 185: 743–754.
548
undifferentiated mesenchymal precursor cells during limb development (23). This discovery suggests that decorin may play a role in dermal condensation during hair follicle development. The staining pattern of decorin shown by the authors was mainly cytoplasmic in the epidermis and in the hair follicle epithelium. Further, another group reported that decorin is detected in total cell extracts from cultured human keratinocytes but not in extracellular matrix extracts (24), which indicates that keratinocytes are unable to secrete decorin. However, the physiological function(s) of intra-cytoplasmic decorin was not clarified in that study. The authors injected rh-decorin into mouse skin and found that it induces anagen onset and catagen delay. Collectively, decorin, which is secreted from cells other than epidermal and hair follicle keratinocytes, might affect the hair cycle. Conditional deletion of the decorin gene in follicular keratinocytes will provide a deeper insight into the effect of decorin in hair follicles and will provide more profound insights of hair biology. Together, in the near future, we expect new progress to solve two critical questions; (i) from the basic aspect, from which component of the skin is the decorin that functions in anagen induction derived?; and (ii) from the clinical aspect, as the injection of decorin works well in murine experiments, can we clinically utilize it for hair loss diseases in humans?
Acknowledgements S Inui and S Itami wrote this manuscript.
Conflict of interests The authors have declared no conflicting interests.
9 Murillas R, Larcher F, Conti C J et al. EMBO J 1995: 14: 5216–5223. 10 Philpott M P, Sanders D A, Kealey T. J Invest Dermatol 1994: 102: 857–861. 11 Jindo T, Tsuboi R, Takamori K et al. J Invest Dermatol 1998: 110: 338–342. 12 Couchman J R. J Invest Dermatol 1993: 101: 60S–64S. 13 Ohyama M, Terunuma A, Tock C L et al. J Clin Invest 2006: 116: 249–260. 14 Bernard B A. Exp Dermatol 2012: 21: 401–403. 15 Foitzik K, Lindner G, Mueller-Roever S et al. FASEB J 2000: 14: 752–760. 16 Inui S, Fukuzato Y, Nakajima T et al. FASEB J 2002: 16: 1967–1969. 17 Yoo H G, Kim J S, Lee S R et al. Biol Pharm Bull 2006: 29: 1246–1250.
18 Inui S, Itami S. Exp Dermatol 2013: 22: 168–171. 19 Shin H, Yoo H G, Inui S et al. BMB Rep 2013: 46: 460–464. 20 Panchaprateep R, Asawanonda P. Exp Dermatol 2014: 23: 216–218. 21 Hu Y, Sun H, Owens R T et al. Neoplasia 2009: 11: 1042–1053. 22 Bichsel K J, Gogia N, Malouff T et al. PLoS ONE 2013: 8: e69368. 23 Lorda-Diez C I, Garcia-Porrero J A, Hurle J M et al. Gene Expr Patterns 2014: 15: 52–60. 24 Velez-DelValle C, Marsch-Moreno M, CastroMunozledo F et al. Biochem Biophys Res Commun 2011: 411: 168–174.
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2014, 23, 547–548
