- Email: [email protected]
Bad Hair Day: Testosterone and Wnts
COMMENTARY
mice, which is essential for HSV-1specific CTL priming. The authors suggest that activation via RANK–RANKL interaction in TG skin prevents HSV-1induced LC apoptosis. Indeed, they confirmed that even 4 days after infection almost all Langerin-positive cells were viable, based on decreased levels of caspase-3 and negative TUNEL staining. In addition, increased numbers of these cells isolated from TG mice downregulate E-cadherin (Klenner et al., 2015). However, the authors failed to show conclusively that these cells are LCs, because CD209 is also expressed by CD103+ dermal DCs, and because depletion of LCs using the Langerindiphtheria toxin receptor mouse model also destroyed them. Previously, RANKL has been implicated in immune regulation and bone homeostasis. Miyahira et al. (2003) showed that administration of soluble RANKL protein markedly enhanced the induction of antigen-specific CTL in Trypanosoma cruzi infection. In the study reported by Klenner et al. (2015), the authors demonstrated that local treatment of WT mice with soluble RANKL is sufficient to reduce disease severity shown by a decrease in skin lesions and virus replication to the level seen in TG mice. Thereby, the authors identify an interesting therapeutic approach that may reduce skin lesion severity and accelerate wound healing. HSV-1 infection is a significant public health problem, one that affects millions worldwide. Despite our growing understanding of the interactions between DCs and HSV-1 and the importance of immunity in primary and recurrent infections, our ability to eliminate the virus or to prevent further spread is still limited. Vaccines are potentially the best tools for achieving this goal; hence, a more comprehensive study of HSV-1 immunization is important (Nikolic and Piguet, 2010). In conclusion, this study by the Loser group provides important insight into the priming and execution of anti-viral immunity to local HSV-1 infection, and it opens new avenues for the use of RANKL as an adjuvant in viral vaccinations. CONFLICT OF INTEREST
The authors state no conflict of interest.
REFERENCES Bedoui S, Greyer M (2014) The role of dendritic cells in immunity against primary herpes simplex virus infections. Front Microbiol 5:533 Iwasaki A (2009) Local advantage: skin DCs prime; skin memory T cells protect. Nat Immunol 10:451–3 Klenner L, Hafezi W, Clausen BE et al. (2015) Cutaneous RANK-RANKL signaling upregulates CD8-mediated anti-viral immunity during Herpes Simplex Virus infection by preventing virus-induced Langerhans cell apoptosis. J Invest Dermatol 135:2676–87 Miyahira Y, Akiba H, Katae M et al. (2003) Cutting edge: a potent adjuvant effect of ligand
to receptor activator of NF-kappa B gene for inducing antigen-specific CD8+ T cell response by DNA and viral vector vaccination. J Immunol 171:6344–8 Nikolic DS, Piguet V (2010) Vaccines and microbicides preventing HIV-1, HSV-2, and HPV mucosal transmission. J Invest Dermatol 130: 352–61 Puttur FK, Fernandez MA, White R et al. (2010) Herpes simplex virus infects skin gamma delta T cells before Langerhans cells and impedes migration of infected Langerhans cells by inducing apoptosis and blocking E-cadherin downregulation. J Immunol 185: 477–87
See related article on pg 2753
Bad Hair Day: Testosterone and Wnts Amanda M. Nelson1 and Luis A. Garza2 Androgens have an important role in normal skin physiology, as well as in the pathogenesis of many skin conditions, such as acne vulgaris, hirsutism, and androgenic alopecia. Kretzchumar et al. (2015) investigate the relationship between androgen receptor (AR) signaling and β-catenin/Wnt signaling pathways in murine hair follicles. Journal of Investigative Dermatology (2015) 135, 2567–2569. doi:10.1038/jid.2015.304
The paradoxical role of androgens in hair follicle biology is not completely understood: androgens trigger hair development at puberty but androgenic alopecia (AGA) in later life. In this issue, Kretzchumar et al. (2015) explore the inhibitory role of androgens by defining a reciprocal relationship between activated β-catenin/Wnt and AR signaling within the hair follicle. Their work identifies AR as a negative regulator of B-catenin signaling, a key signaling pathway in hair cycling and development. The AR belongs to the superfamily of nuclear hormone receptors. Upon binding to the AR, testosterone or its more potent product, 5α-dihydrotestosterone (5α-DHT), undergoes a conformational change, and the ligand/AR complex translocates from the cytosol to the nucleus where it controls transcription of AR target genes. The activity of AR is
controlled by coregulatory proteins that influence ligand specificity and DNAbinding capacity (Heinlein and Chang, 2002a). However, the AR may also trigger rapid, non-genomic effects when present in the cytoplasm, including activation of the mitogen-activated protein kinase cascade and regulation of intracellular calcium levels (Heinlein and Chang, 2002b). The AR is widely expressed in the skin and, in particular, within the androgen-responsive skin appendages: sweat glands, sebaceous glands, and hair follicles. Numerous studies have characterized AR expression in the skin, although a true consensus on AR expression within the skin and its specific cell types is lacking, as the results vary, depending on the models, reagents, and methods used to detect its expression (i.e., qPCR or immunohistochemistry, human vs. mouse). As pointed out by
1
Department of Dermatology, Penn State Hershey College of Medicine, Hershey, Pennsylvania, USA and Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
2
Correspondence: Luis A. Garza, Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. E-mail: [email protected]
www.jidonline.org 2567
COMMENTARY
Kretzchumar et al. (2015), differences likely also exist between AR activity in mouse and human skin. Cutaneous androgen metabolism occurs within sweat glands, sebaceous glands, and hair follicles where androgens are synthesized de novo from cholesterol or through the conversion of dehydroepiandrosterone sulfate (DHEA-S) and dehydroepiandrosterone (DHEA)—weaker circulating androgens produced by the adrenal gland. All isoforms of the enzymes required to produce and degrade testosterone and 5α-DHT are present within the pilosebaceous unit. These include steroid sulfatase, 3β-hydroxysterioid dehydrogenase (HSD), 17β-HSD, 5α-reductase, 3α-HSD, and aromatase. The expression and activity of these enzymes varies between males and females, body location (scalp versus face), and even anatomical structure (hair follicle versus sebaceous gland). For example, type 1 5α-reductase is expressed predominantly within the sebaceous gland, whereas type 2 5α-reductase is located in hair follicles. Differences in expression and activity of these enzymes indicate a tight regulatory process for androgen metabolism within the skin. For a detailed review of androgen metabolism in the skin, see Chen, et al., 2002. The β-catenin/Wnt signaling pathway is critical to the development of both hair follicles and sebaceous glands. Epidermal stem cells reside within the bulge region of the pilosebaceous unit and can give rise to progeny that differentiate along multiple cell lineages, including epidermal and follicular keratinocytes as well as sebaceous glands. As daughter cells migrate from the bulge region, the Wnt/wingless (Wnt) and Sonic Hedgehog (Shh) signaling pathways are intricately involved in these cell fate decisions. Cells destined to become sebocytes have increased Shh and Myc signaling and decreased Wnt signaling, whereas cells destined to become hair follicles have increased βcatenin/Wnt signaling. In transgenic mouse models, intact Wnt signaling promotes hair follicle differentiation, whereas inhibition of Wnt signaling through the prevention of Lef1/β-catenin interaction leads to sebocyte
differentiation. Similarly, inactivating mutations in LEF1 are commonly found in sebaceous tumors. (Takeda et al., 2006) Regulation of the β-catenin/Wnt signaling pathway is key. In their manuscript, Kretzchumar et al. (2015), investigate the relationship between AR signaling and β-catenin/wnt signaling in mouse hair follicle bulb cells. The authors characterize the expression of β- catenin and AR within the epidermis and the dermis, concentrating on the hair follicle. They observe that AR and β-catenin display almost reciprocal patterns of expression––such that, when β-catenin is expressed within the nucleus, AR is localized to the cytoplasm and vice versa. These findings are especially notable during the anagen phase of the cell cycle, during which nuclear expression of β-catenin was localized to the upper bulb cells of the hair follicle, whereas AR expression was limited to the dermal papillae cells. During the telogen and catagen phases, β-catenin was absent from the nucleus in hair follicle bulb cells, but AR was detected. This shift in subcellular location highlights the potential importance of each signaling pathway controlling the phases of the hair cycle. To study the role of AR modulation of β-catenin expression and activity, the authors used a combination of in vitro and in vivo methods. In cell culture, they transfect immortalized sebocytes (SebE6E7) with the TOPFLASH Wnt reporter system, as sebaceous glands are highly responsive to androgens. They also treat transgenic mouse lines with conditional activated β- catenin (ΔK5ΔNβ-cateninER, ΔK14ΔNβ-cateninER, and ΔK15ΔNβ-cateninER) with a combination of testosterone, an AR activator, or bicalutamide, a potent AR antagonist. Altogether, their data strongly implicate AR as a negative regulator of β-catenin/ Wnt-dependent transcription. These findings bring up some interesting points. First, what is the balance of AR regulation in hair follicle and sebaceous gland development? The roles that androgens have in the development and growth of sebaceous glands, sebum production, and acne vulgaris are well established (Pochi and Strauss, 1969). Wnt signaling is
2568 Journal of Investigative Dermatology (2015), Volume 135
decreased within progenitor cells that develop into sebocytes (Takeda et al., 2006). As the data shown by Kretzchumar et al. (2015, this issue) demonstrate one mechanism by which androgens may contribute to sebaceous gland hyperplasia is through inhibition of the Wnt signaling pathway. However, sebaceous gland hyperplasia was a more subtle finding in the present study. This is likely because the authors concentrated on androgen treatment effects on the hair follicle and during continuous β-catenin signaling. Future studies focused on the sebaceous gland response, which employ the strategy of combining genetic models (like loss-offunction β-catenin) with pharmacologic treatments (such as androgen agonists and antagonists) may be interesting. What are the clinical implications of this work? Androgens stimulate terminal beard hair, axillary hair, and pubic hair growth after puberty, yet trigger follicle miniaturization in AGA in later life—the androgen paradox. This paradox can be extended to the present work: is regulation of β-catenin/Wnt pathway by AR in these two polar opposite conditions different? With the high levels of androgens detected within the hair follicle bulb in AGA, it is likely that β-catenin/ Wnt signaling is inhibited, consistent with the enlarged sebaceous glands observed in AGA-affected scalp. In contrast, during puberty in the axillae, e.g., modified androgen metabolism and signaling likely allow for preferential development of hair follicles over sebaceous glands. Additional work is still needed to fully understand the androgen paradox. Besides the above, the mechanistic insights provided by Kretzchumar et al. (2015, this issue), open new biologic questions and therapeutic avenues for the treatment of hair and sebaceous gland disorders. What is the detailed mechanism by which testosterone antagonizes the β-catenin pathway here? As suggested by Kretzchumar et al., it is most likely an indirect mechanism. Prostaglandins are possibly one underexplored area for this indirect regulation. For example, the Ptgs/PGE2 pathway is implicated gastric tumorigenesis by increasing activation of the Wnt signaling pathway.
COMMENTARY
Clinical Implications
systems: lessons learned from mice lacking AR in specific cells. Nucl Recept Signal 11 e001
●
Testosterone antagonizes the Wnt pathway, which is important for hair function.
●
Inhibition of testosterone can enhance Wnt pathway activity.
●
While not universally applicable, these results suggest possible mechanisms of androgenetic alopecia pathogenesis.
Prostaglandins also influence the hair cycle, with prostaglandin F2a (PGF2α) triggering eyelash growth, whereas prostaglandin D2 decreases hair growth and is also significantly elevated in bald scalp of AGA (Garza et al., 2012). In several contexts an enzyme that synthesizes PGD2 (Ptgds) has been shown to be induced by testosterone. As different prostaglandins have opposing biological effects, PGD2 may mediate testosterone inhibition of Wnt signaling in AGA. Future studies are needed to test this hypothesis. Androgens influence many physiological processes including the development of the immune, nervous, skeletal, and muscle systems (Chang et al., 2013). In addition to all the traditional effects on the skin (i.e., development of acne and AGA), androgens also have a key role in wound healing. In mouse models in which AR signaling is inhibited by castration, 5α-reductase inhibition, or AR-null mice, wound healing was accelerated (Ashcroft and Mills, 2002). The findings by Kretzchumar et al., (2015) may provide the explanation for this accelerated wound healing in the absence of AR, in that β-catenin/Wnt signaling is critical for wound repair (Bielefeld et al., 2013). It is interesting to speculate that AR roles in other physiological processes may be tied to its role as a β-catenin/Wnt inhibitor. All in all, using a combination of in vitro and in vivo models, Kretzchumar et al. (2015), provided us with mechanistic insight into the roles of androgens and β-catenin/Wnt signaling in mouse hair follicles. With follow-up and confirmatory studies in humans, we may be one step closer to understanding the full pathology associated with androgen-mediated skin diseases. CONFLICT OF INTEREST
The authors state no conflict of interest.
ACKNOWLEDGMENTS This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, part of the National Institutes of Health, under Award Number F32AR062932 to AMN and R01AR064297 to LAG.
REFERENCES Ashcroft GS, Mills SJ (2002) Androgen receptormediated inhibition of cutaneous wound healing. J Clin Invest 110 615–24. PMID: 12208862 Bielefeld KA, Amini-Nik S, Alman BA (2013) Cutaneous wound healing: recruiting developmental pathways for regeneration. Cell Mol Life Sci 70 2059–81 Chang C, Yeh S, Lee SO et al. (2013) Androgen receptor (AR) pathophysiological roles in androgen-related diseases in skin, bone/muscle, metabolic syndrome and neuron/immune
Chen W, Thiboutot D, Zouboulis CC (2002) Cutaneous androgen metabolism: basic research and clinical perspectives. J Investig Dermatol Symp Proc 119:992–1007 Garza LA, Liu Y, Yang Z et al. (2012) Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia. Sci Transl Med 4 126ra34 Heinlein CA, Chang C (2002a) Androgen receptor (AR) coregulators: an overview. Endocr Rev 23 175–200 Heinlein CA, Chang C (2002b) The roles of androgen receptors and androgen-binding proteins in nongenomic androgen actions. Mol Endocrinol 16 2181–7 Kretzchumar K, Cottle D, Schweiger P et al. (2015) The androgen receptor antagonizes Wnt/B-catenin signaling in epidermal stem cells. J Invest Dermatol 135:2753–63 Pochi PE, Strauss JS (1969) Sebaceous gland response in man to the administration of testosterone, delta-4-androstenedione, and dehydroisoandrosterone. J Investig Dermatol Symp Proc 52:32–6. Takeda H, Lyle S, Lazar AJ (2006) Human sebaceous tumors harbor inactivating mutations in LEF1. Nat Med 12 395–7
See related article on pg 2852
Filamin A Mediates Wound Closure by Promoting Elastic Deformation and Maintenance of Tension in the Collagen Matrix Geoffrey C. Gurtner1 and Victor W. Wong1 Fibroblasts have a central role in wound healing via matrix production, remodeling, and contraction. Their role as mechanoresponsive cells during tissue repair is evident, but the molecular mechanisms of this process remain uncertain. Filamin A, an intracellular protein that stabilizes the actin cytoskeleton regulates fibroblast-matrix interactions. Fibroblast defects in cytoskeletal dynamics may underlie key aspects of chronic wound pathophysiology. Journal of Investigative Dermatology (2015) 135, 2569–2571. doi:10.1038/jid.2015.327
Chronic wound burden
Impairments in the cutaneous response to injury can result in chronic wounds, a
growing global health burden exacerbated by the rise of diabetic, obese, and elderly populations. In the United States
1
Division of Plastic Surgery, Department of Surgery, School of Medicine, Stanford University, Stanford, California, USA Correspondence: Geoffrey C. Gurtner, Division of Plastic Surgery, Department of Surgery, School of Medicine, Stanford University, 257 Campus Drive West, Stanford, California 94305, USA. E-mail: [email protected]
www.jidonline.org 2569
mice, which is essential for HSV-1specific CTL priming. The authors suggest that activation via RANK–RANKL interaction in TG skin prevents HSV-1induced LC apoptosis. Indeed, they confirmed that even 4 days after infection almost all Langerin-positive cells were viable, based on decreased levels of caspase-3 and negative TUNEL staining. In addition, increased numbers of these cells isolated from TG mice downregulate E-cadherin (Klenner et al., 2015). However, the authors failed to show conclusively that these cells are LCs, because CD209 is also expressed by CD103+ dermal DCs, and because depletion of LCs using the Langerindiphtheria toxin receptor mouse model also destroyed them. Previously, RANKL has been implicated in immune regulation and bone homeostasis. Miyahira et al. (2003) showed that administration of soluble RANKL protein markedly enhanced the induction of antigen-specific CTL in Trypanosoma cruzi infection. In the study reported by Klenner et al. (2015), the authors demonstrated that local treatment of WT mice with soluble RANKL is sufficient to reduce disease severity shown by a decrease in skin lesions and virus replication to the level seen in TG mice. Thereby, the authors identify an interesting therapeutic approach that may reduce skin lesion severity and accelerate wound healing. HSV-1 infection is a significant public health problem, one that affects millions worldwide. Despite our growing understanding of the interactions between DCs and HSV-1 and the importance of immunity in primary and recurrent infections, our ability to eliminate the virus or to prevent further spread is still limited. Vaccines are potentially the best tools for achieving this goal; hence, a more comprehensive study of HSV-1 immunization is important (Nikolic and Piguet, 2010). In conclusion, this study by the Loser group provides important insight into the priming and execution of anti-viral immunity to local HSV-1 infection, and it opens new avenues for the use of RANKL as an adjuvant in viral vaccinations. CONFLICT OF INTEREST
The authors state no conflict of interest.
REFERENCES Bedoui S, Greyer M (2014) The role of dendritic cells in immunity against primary herpes simplex virus infections. Front Microbiol 5:533 Iwasaki A (2009) Local advantage: skin DCs prime; skin memory T cells protect. Nat Immunol 10:451–3 Klenner L, Hafezi W, Clausen BE et al. (2015) Cutaneous RANK-RANKL signaling upregulates CD8-mediated anti-viral immunity during Herpes Simplex Virus infection by preventing virus-induced Langerhans cell apoptosis. J Invest Dermatol 135:2676–87 Miyahira Y, Akiba H, Katae M et al. (2003) Cutting edge: a potent adjuvant effect of ligand
to receptor activator of NF-kappa B gene for inducing antigen-specific CD8+ T cell response by DNA and viral vector vaccination. J Immunol 171:6344–8 Nikolic DS, Piguet V (2010) Vaccines and microbicides preventing HIV-1, HSV-2, and HPV mucosal transmission. J Invest Dermatol 130: 352–61 Puttur FK, Fernandez MA, White R et al. (2010) Herpes simplex virus infects skin gamma delta T cells before Langerhans cells and impedes migration of infected Langerhans cells by inducing apoptosis and blocking E-cadherin downregulation. J Immunol 185: 477–87
See related article on pg 2753
Bad Hair Day: Testosterone and Wnts Amanda M. Nelson1 and Luis A. Garza2 Androgens have an important role in normal skin physiology, as well as in the pathogenesis of many skin conditions, such as acne vulgaris, hirsutism, and androgenic alopecia. Kretzchumar et al. (2015) investigate the relationship between androgen receptor (AR) signaling and β-catenin/Wnt signaling pathways in murine hair follicles. Journal of Investigative Dermatology (2015) 135, 2567–2569. doi:10.1038/jid.2015.304
The paradoxical role of androgens in hair follicle biology is not completely understood: androgens trigger hair development at puberty but androgenic alopecia (AGA) in later life. In this issue, Kretzchumar et al. (2015) explore the inhibitory role of androgens by defining a reciprocal relationship between activated β-catenin/Wnt and AR signaling within the hair follicle. Their work identifies AR as a negative regulator of B-catenin signaling, a key signaling pathway in hair cycling and development. The AR belongs to the superfamily of nuclear hormone receptors. Upon binding to the AR, testosterone or its more potent product, 5α-dihydrotestosterone (5α-DHT), undergoes a conformational change, and the ligand/AR complex translocates from the cytosol to the nucleus where it controls transcription of AR target genes. The activity of AR is
controlled by coregulatory proteins that influence ligand specificity and DNAbinding capacity (Heinlein and Chang, 2002a). However, the AR may also trigger rapid, non-genomic effects when present in the cytoplasm, including activation of the mitogen-activated protein kinase cascade and regulation of intracellular calcium levels (Heinlein and Chang, 2002b). The AR is widely expressed in the skin and, in particular, within the androgen-responsive skin appendages: sweat glands, sebaceous glands, and hair follicles. Numerous studies have characterized AR expression in the skin, although a true consensus on AR expression within the skin and its specific cell types is lacking, as the results vary, depending on the models, reagents, and methods used to detect its expression (i.e., qPCR or immunohistochemistry, human vs. mouse). As pointed out by
1
Department of Dermatology, Penn State Hershey College of Medicine, Hershey, Pennsylvania, USA and Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
2
Correspondence: Luis A. Garza, Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. E-mail: [email protected]
www.jidonline.org 2567
COMMENTARY
Kretzchumar et al. (2015), differences likely also exist between AR activity in mouse and human skin. Cutaneous androgen metabolism occurs within sweat glands, sebaceous glands, and hair follicles where androgens are synthesized de novo from cholesterol or through the conversion of dehydroepiandrosterone sulfate (DHEA-S) and dehydroepiandrosterone (DHEA)—weaker circulating androgens produced by the adrenal gland. All isoforms of the enzymes required to produce and degrade testosterone and 5α-DHT are present within the pilosebaceous unit. These include steroid sulfatase, 3β-hydroxysterioid dehydrogenase (HSD), 17β-HSD, 5α-reductase, 3α-HSD, and aromatase. The expression and activity of these enzymes varies between males and females, body location (scalp versus face), and even anatomical structure (hair follicle versus sebaceous gland). For example, type 1 5α-reductase is expressed predominantly within the sebaceous gland, whereas type 2 5α-reductase is located in hair follicles. Differences in expression and activity of these enzymes indicate a tight regulatory process for androgen metabolism within the skin. For a detailed review of androgen metabolism in the skin, see Chen, et al., 2002. The β-catenin/Wnt signaling pathway is critical to the development of both hair follicles and sebaceous glands. Epidermal stem cells reside within the bulge region of the pilosebaceous unit and can give rise to progeny that differentiate along multiple cell lineages, including epidermal and follicular keratinocytes as well as sebaceous glands. As daughter cells migrate from the bulge region, the Wnt/wingless (Wnt) and Sonic Hedgehog (Shh) signaling pathways are intricately involved in these cell fate decisions. Cells destined to become sebocytes have increased Shh and Myc signaling and decreased Wnt signaling, whereas cells destined to become hair follicles have increased βcatenin/Wnt signaling. In transgenic mouse models, intact Wnt signaling promotes hair follicle differentiation, whereas inhibition of Wnt signaling through the prevention of Lef1/β-catenin interaction leads to sebocyte
differentiation. Similarly, inactivating mutations in LEF1 are commonly found in sebaceous tumors. (Takeda et al., 2006) Regulation of the β-catenin/Wnt signaling pathway is key. In their manuscript, Kretzchumar et al. (2015), investigate the relationship between AR signaling and β-catenin/wnt signaling in mouse hair follicle bulb cells. The authors characterize the expression of β- catenin and AR within the epidermis and the dermis, concentrating on the hair follicle. They observe that AR and β-catenin display almost reciprocal patterns of expression––such that, when β-catenin is expressed within the nucleus, AR is localized to the cytoplasm and vice versa. These findings are especially notable during the anagen phase of the cell cycle, during which nuclear expression of β-catenin was localized to the upper bulb cells of the hair follicle, whereas AR expression was limited to the dermal papillae cells. During the telogen and catagen phases, β-catenin was absent from the nucleus in hair follicle bulb cells, but AR was detected. This shift in subcellular location highlights the potential importance of each signaling pathway controlling the phases of the hair cycle. To study the role of AR modulation of β-catenin expression and activity, the authors used a combination of in vitro and in vivo methods. In cell culture, they transfect immortalized sebocytes (SebE6E7) with the TOPFLASH Wnt reporter system, as sebaceous glands are highly responsive to androgens. They also treat transgenic mouse lines with conditional activated β- catenin (ΔK5ΔNβ-cateninER, ΔK14ΔNβ-cateninER, and ΔK15ΔNβ-cateninER) with a combination of testosterone, an AR activator, or bicalutamide, a potent AR antagonist. Altogether, their data strongly implicate AR as a negative regulator of β-catenin/ Wnt-dependent transcription. These findings bring up some interesting points. First, what is the balance of AR regulation in hair follicle and sebaceous gland development? The roles that androgens have in the development and growth of sebaceous glands, sebum production, and acne vulgaris are well established (Pochi and Strauss, 1969). Wnt signaling is
2568 Journal of Investigative Dermatology (2015), Volume 135
decreased within progenitor cells that develop into sebocytes (Takeda et al., 2006). As the data shown by Kretzchumar et al. (2015, this issue) demonstrate one mechanism by which androgens may contribute to sebaceous gland hyperplasia is through inhibition of the Wnt signaling pathway. However, sebaceous gland hyperplasia was a more subtle finding in the present study. This is likely because the authors concentrated on androgen treatment effects on the hair follicle and during continuous β-catenin signaling. Future studies focused on the sebaceous gland response, which employ the strategy of combining genetic models (like loss-offunction β-catenin) with pharmacologic treatments (such as androgen agonists and antagonists) may be interesting. What are the clinical implications of this work? Androgens stimulate terminal beard hair, axillary hair, and pubic hair growth after puberty, yet trigger follicle miniaturization in AGA in later life—the androgen paradox. This paradox can be extended to the present work: is regulation of β-catenin/Wnt pathway by AR in these two polar opposite conditions different? With the high levels of androgens detected within the hair follicle bulb in AGA, it is likely that β-catenin/ Wnt signaling is inhibited, consistent with the enlarged sebaceous glands observed in AGA-affected scalp. In contrast, during puberty in the axillae, e.g., modified androgen metabolism and signaling likely allow for preferential development of hair follicles over sebaceous glands. Additional work is still needed to fully understand the androgen paradox. Besides the above, the mechanistic insights provided by Kretzchumar et al. (2015, this issue), open new biologic questions and therapeutic avenues for the treatment of hair and sebaceous gland disorders. What is the detailed mechanism by which testosterone antagonizes the β-catenin pathway here? As suggested by Kretzchumar et al., it is most likely an indirect mechanism. Prostaglandins are possibly one underexplored area for this indirect regulation. For example, the Ptgs/PGE2 pathway is implicated gastric tumorigenesis by increasing activation of the Wnt signaling pathway.
COMMENTARY
Clinical Implications
systems: lessons learned from mice lacking AR in specific cells. Nucl Recept Signal 11 e001
●
Testosterone antagonizes the Wnt pathway, which is important for hair function.
●
Inhibition of testosterone can enhance Wnt pathway activity.
●
While not universally applicable, these results suggest possible mechanisms of androgenetic alopecia pathogenesis.
Prostaglandins also influence the hair cycle, with prostaglandin F2a (PGF2α) triggering eyelash growth, whereas prostaglandin D2 decreases hair growth and is also significantly elevated in bald scalp of AGA (Garza et al., 2012). In several contexts an enzyme that synthesizes PGD2 (Ptgds) has been shown to be induced by testosterone. As different prostaglandins have opposing biological effects, PGD2 may mediate testosterone inhibition of Wnt signaling in AGA. Future studies are needed to test this hypothesis. Androgens influence many physiological processes including the development of the immune, nervous, skeletal, and muscle systems (Chang et al., 2013). In addition to all the traditional effects on the skin (i.e., development of acne and AGA), androgens also have a key role in wound healing. In mouse models in which AR signaling is inhibited by castration, 5α-reductase inhibition, or AR-null mice, wound healing was accelerated (Ashcroft and Mills, 2002). The findings by Kretzchumar et al., (2015) may provide the explanation for this accelerated wound healing in the absence of AR, in that β-catenin/Wnt signaling is critical for wound repair (Bielefeld et al., 2013). It is interesting to speculate that AR roles in other physiological processes may be tied to its role as a β-catenin/Wnt inhibitor. All in all, using a combination of in vitro and in vivo models, Kretzchumar et al. (2015), provided us with mechanistic insight into the roles of androgens and β-catenin/Wnt signaling in mouse hair follicles. With follow-up and confirmatory studies in humans, we may be one step closer to understanding the full pathology associated with androgen-mediated skin diseases. CONFLICT OF INTEREST
The authors state no conflict of interest.
ACKNOWLEDGMENTS This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, part of the National Institutes of Health, under Award Number F32AR062932 to AMN and R01AR064297 to LAG.
REFERENCES Ashcroft GS, Mills SJ (2002) Androgen receptormediated inhibition of cutaneous wound healing. J Clin Invest 110 615–24. PMID: 12208862 Bielefeld KA, Amini-Nik S, Alman BA (2013) Cutaneous wound healing: recruiting developmental pathways for regeneration. Cell Mol Life Sci 70 2059–81 Chang C, Yeh S, Lee SO et al. (2013) Androgen receptor (AR) pathophysiological roles in androgen-related diseases in skin, bone/muscle, metabolic syndrome and neuron/immune
Chen W, Thiboutot D, Zouboulis CC (2002) Cutaneous androgen metabolism: basic research and clinical perspectives. J Investig Dermatol Symp Proc 119:992–1007 Garza LA, Liu Y, Yang Z et al. (2012) Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia. Sci Transl Med 4 126ra34 Heinlein CA, Chang C (2002a) Androgen receptor (AR) coregulators: an overview. Endocr Rev 23 175–200 Heinlein CA, Chang C (2002b) The roles of androgen receptors and androgen-binding proteins in nongenomic androgen actions. Mol Endocrinol 16 2181–7 Kretzchumar K, Cottle D, Schweiger P et al. (2015) The androgen receptor antagonizes Wnt/B-catenin signaling in epidermal stem cells. J Invest Dermatol 135:2753–63 Pochi PE, Strauss JS (1969) Sebaceous gland response in man to the administration of testosterone, delta-4-androstenedione, and dehydroisoandrosterone. J Investig Dermatol Symp Proc 52:32–6. Takeda H, Lyle S, Lazar AJ (2006) Human sebaceous tumors harbor inactivating mutations in LEF1. Nat Med 12 395–7
See related article on pg 2852
Filamin A Mediates Wound Closure by Promoting Elastic Deformation and Maintenance of Tension in the Collagen Matrix Geoffrey C. Gurtner1 and Victor W. Wong1 Fibroblasts have a central role in wound healing via matrix production, remodeling, and contraction. Their role as mechanoresponsive cells during tissue repair is evident, but the molecular mechanisms of this process remain uncertain. Filamin A, an intracellular protein that stabilizes the actin cytoskeleton regulates fibroblast-matrix interactions. Fibroblast defects in cytoskeletal dynamics may underlie key aspects of chronic wound pathophysiology. Journal of Investigative Dermatology (2015) 135, 2569–2571. doi:10.1038/jid.2015.327
Chronic wound burden
Impairments in the cutaneous response to injury can result in chronic wounds, a
growing global health burden exacerbated by the rise of diabetic, obese, and elderly populations. In the United States
1
Division of Plastic Surgery, Department of Surgery, School of Medicine, Stanford University, Stanford, California, USA Correspondence: Geoffrey C. Gurtner, Division of Plastic Surgery, Department of Surgery, School of Medicine, Stanford University, 257 Campus Drive West, Stanford, California 94305, USA. E-mail: [email protected]
www.jidonline.org 2569