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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 6 2875-2880
Copyright © 2001 by The Endocrine Society

Other Original Studies

5{alpha}-Reductase Type 2 Is Constitutively Expressed in the Dermal Papilla and Connective Tissue Sheath of the Hair Follicle in Vivo But Not during Culture in Vitro1

Yuji Asada, Tadashige Sonoda, Mayumi Ojiro, Sotaro Kurata, Toshihiro Sato, Tetsuo Ezaki and Susumu Takayasu

Department of Dermatology (Y.A., T.So., M.O., S.K., T.Sa., S.T.), Oita Medical University; and Ezaki Clinic (T.E.), Oita 879-5593 , Japan

Address all correspondence and requests for reprints to: Yuji Asada, M.D., Oita Medical University, Department of Dermatology, 1-1 Daigaoka, Hasama-Machi, Oita 879-5593, Japan. E-mail: asada{at}oita-med.ac.jp

Abstract

Recent studies suggest that 5{alpha}-reductase type 2 (5{alpha}R2) rather than 5{alpha}R1 plays a key role in the pathogenesis of male-pattern baldness. To clarify the localization of the androgen receptor (AR), 5{alpha}R1, and 5{alpha}R2 in the hair follicle, we investigated the expression of the corresponding genes by RT-PCR using microdissected hair follicles. AR and 5{alpha}R1 mRNAs were expressed in all portions of the hair follicle. By contrast, 5{alpha}R2 mRNA was expressed only in mesenchymal portions that included the dermal papilla and connective tissue sheath, and hardly any was expressed in epithelial portions. The intensity of expression of these genes in each portion of the hair follicles did not differ between follicles from balding and nonbalding scalp. We also examined the expression of these genes in cultured fibroblasts derived from the dermal papilla and connective tissue sheath. Although expression of AR and 5{alpha}R1 mRNAs was easily detected, there was no obvious expression of 5{alpha}R2 mRNA in either type of cell. Type-specific inhibition of 5{alpha}R activity by MK386 and MK906 confirmed these patterns of expression of 5{alpha}R mRNA. Thus, the expression of 5{alpha}R2 mRNA seems to be characteristic of freshly microdissected mesenchymal portions of the hair follicle, but such expression might not be maintained in culture.

ANDROGENS EXERT THEIR biological effects on their target cells as testosterone or dihydrotestosterone (DHT). The latter, the more potent androgen, is generated from testosterone by the enzyme steroid 5{alpha}-reductase (5{alpha}R). DHT binds to the androgen receptor (AR) with higher affinity than testosterone, and the resultant complex is more stable than the testosterone-AR complex. Thus, DHT plays a major role in the effects of androgens (1, 2).

There is much evidence to suggest that male-pattern baldness develops under the influence of androgens. Hypogonadal men or those castrated before puberty do not become bald, but such men begin to lose their hair when treated chronically with testosterone (3, 4). Moreover, XY individuals with testicular feminization, who have nonfunctional AR but normal male levels of circulating testosterone, have a female phenotype and do not develop male-pattern baldness (5, 6). Many target organs of androgens in men, including the prostate, are more responsive to DHT than to testosterone.

There are two isoforms of human 5{alpha}R, namely, type 1 (5{alpha}R1) and type 2 (5{alpha}R2). 5{alpha}R1, which is encoded by the SRD5A1 gene and is composed of 259 amino acids, has an optimum pH of 6–9, whereas 5{alpha}R2, encoded by the SRD5A2 gene and composed of 254 amino acids, has an optimum pH of 5.5. 5{alpha}R1 has been detected in various androgen-independent organs, such as the liver and brain (1). By contrast, 5{alpha}R2 is found predominantly in androgen-dependent organs, such as the epididymis and prostate (1). It is generally believed that 5{alpha}R1 and 5{alpha}R2 play a catabolic and an anabolic role, respectively, in the metabolism and action of androgens (1). 5{alpha}R2, rather than 5{alpha}R1, is thought to be important in the development of male-pattern baldness: male pseudohermaphrodites with 5{alpha}R2 deficiency do not develop male-pattern baldness (7, 8, 9). Furthermore, clinical studies have shown that a selective inhibitor of 5{alpha}R2, finasteride, promotes hair growth in men with male-pattern baldness in parallel with decreased levels of DHT in scalp skin (10, 11).

A hair follicle consists of epithelial components, which include the inner and outer root sheath (ORS) and hair shaft, and mesenchymal components, which include the dermal papilla (DP) and connective tissue sheath that form a three-dimensional tube. In the bulbar portion, proliferating cells of the primitive epithelial matrix envelope the DP. The DP and the upper portion of the follicle remain throughout the hair cycle, whereas the lower follicle undergoes a cyclic pattern of growth (anagen), regression (catagen), and resting (telogen). The interaction between cells of the DP and those of the matrix is considered to play an important role in this cycle. Moreover, in the morphogenesis of embryonic hair, the first inductive signal is thought to be of mesenchymal origin, instructing ectoderm to form a hair germ. In hair follicles of adult vibrissae, dermal papillae have the capacity to form new hair follicles (12).

In male-pattern baldness, the hair shaft gradually becomes thinner and the anagen phase becomes shorter during repeated hair cycles. DP cells have recently been shown to produce androgen-dependent biological factors that modulate the proliferation of follicular epithelial cells (13, 14).

The various findings described above suggest that the action of androgen in hair follicles is mediated via the DP. However, neither the localization of 5{alpha}R isozymes nor that of AR in human hair follicles has yet been clarified, in particular, in male-pattern baldness. To determine the localization of 5{alpha}R isozymes and AR in hair follicles, we examined the levels of the corresponding mRNAs in various portions of hair follicles that had been freshly dissected from balding and nonbalding scalp by semiquantitative RT-PCR. We also studied the expression of AR, 5{alpha}R1, and 5{alpha}R2 mRNAs and the activity of the isozymes in cultured mesenchymal cells to determine whether the various genes are expressed in culture.

Materials and Methods

Dissection of hair follicles into five portions

Hair follicles at the anagen phase were isolated from balding (five samples) and nonbalding (seven samples) scalp skin of 12 individuals who were undergoing plastic surgery for male-pattern baldness or resection of benign tumors after provision of written informed consent approved by the ethical committee of Oita Medical University (Table 1Go). Each hair follicle was dissected into five portions: the DP; the lower connective tissue sheath (LCTS); the matrix portion surrounding the DP that contained matrix cells (MX); the upper epithelial portion, which included the hair shaft and inner and ORS; and the upper connective tissue sheath, under a light microscope as described previously (16). In brief, each hair follicle was cut horizontally immediately above the tip of the DP. Then the LCTS of the bulbar portion was inverted and the loosely surrounding matrix portion was dissected from the DP. The DP was cut off from the inverted LCTS at the base of the papilla. The remaining upper epithelial and mesenchymal portions were loosely attached to each other, and they were easily separated mechanically (Fig. 1Go). Contamination of each portion by the others was confirmed histologically to be negligible, as demonstrated previously (16).


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  		Table 1. List of donors of hair follicles

 


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  		Figure 1. The five portions dissected from individual hair follicles. First, hair follicles were isolated from scalp skin and cut just below the sebaceous glands (a). Each hair follicle was cut horizontally above the tip of the DP (b), and the surrounding matrix portion (MX) was dissected from the bulbar portion. The LCTS was inverted (c), and then the DP was cut off from the LCTS. The remaining portion was easily divided into the inner and outer root sheath (IRS/ORS) that included the hair shaft and the upper connective tissue sheath (UCTS).

 
Cell culture

Individual dermal papillae were isolated from hair follicles of the anagen stage under a light microscope and put into explant culture (17, 18). Fibroblasts derived from the connective tissue sheath were also cultured in a similar manner. Cells were grown in DMEM supplemented with 10% FBS, 20 mM L-glutamine, 50 U/mL penicillin, and 50 µg/mL streptomycin in a humidified atmosphere of 5% CO2 in air at 37 C.

Semiquantitative analysis of the expression of mRNAs for the 5{alpha}R isozymes and AR by RT-PCR

The individual five portions dissected from about 20 hair follicles per skin sample were pooled to yield five samples per individual for analysis. Total RNA was extracted from each pooled sample and from cultured cells with ISOGEN (Nippon Gene, Tokyo, Japan) according to the manufacturer’s instructions. The RNA was dissolved in double-distilled water, which had been treated with diethyl pyrocarbonate, and stored at -70 C. cDNA was synthesized as follows. One microgram of total RNA and 0.5 µg of oligo primers (Promega Corp., Madison, WI) were heated to 70 C for 10 min in 17 µL of diethyl pyrocarbonate-treated double-distilled water. After chilling on ice for 2 min, the mixture was supplemented with the reaction buffer to give a final volume of 40 µL. The final reaction mixture included 400 U Moloney murine leukemia virus reverse transcriptase (Life Technologies, Rockville, MD), 10–40 U RNase inhibitor (WAKO, Osaka, Japan), 0.5 mM dNTPs (TAKARA, Kyoto, Japan), 50 mM Tris-HCl (pH 8.3), 75 mM KCl, 3 mM MgCl2, and 10 mM dithiothreitol. The final mixture was incubated at 42 C for 1 h and then heated at 70 C for 10 min to inactivate the enzyme. The cDNA was amplified by PCR, with 30 cycles, in a thermal cycler (ASTEC, Fukuoka, Japan). The 25 µL aliquots of the reaction mixture for PCR contained 0.65 U of Taq DNA polymerase (TAKARA), 200 µM dNTPs, 0.5 µM sense and antisense primers, 50 mM KCl, 10 mM Tris-HCl (pH 8.3), 1 mM MgCl2, and 0.5 µL of cDNA as template. The nucleotide sequences of primers used for amplification were as follows: For AR, the sense and antisense primers were 5'-CTCTCTCAAGAGTTTGGATGGCT-3' and 5'-CACTTGCACAGAGATGATCTCTGC-3', respectively; for 5{alpha}R1, they were 5'-CAATGGCGCTTCTCTATGG-3' and 5'-TACACACAGCACCTGACACG-3'; for 5{alpha}R2, they were 5'-TGAGGTTACATGCTGCTTGC-3' and 5'-TCCAATTACAAGCGTTCGG-3'; and for glyceraldehyde-3-phosphate dehydrogenase (GAPDH), they were 5'-CCCATCACCATCTTCCAG-3' and 5'-CCTGCTTCACCACCTTCT-3'. Each cycle of PCR was programmed for denaturation (94 C; 1 min), annealing (55 C; 1 min) and extension (72 C; 1 min), with the exception that the first denaturation step was allowed to proceed for 5 min, and the final extension step for 3 min. Twenty microliters of each reaction mixture after PCR were combined with 100 µL of 0.4 N NaOH, neutralized with an equal volume of cold 2 M ammonium acetate, and transferred to a nylon membrane (Hybond N+; Amersham Pharmacia Biotech, Tokyo, Japan) through a slot window of a blotting apparatus (Bio-Rad Laboratories, Inc., Hercules, CA) according to the manufacturer’s instructions. After UV-cross-linking at 312 nm, the amplified fragments on the membrane were allowed to hybridize with oligonucleotide probes specific for AR or 5{alpha}R1 or 5{alpha}R2 cDNAs, which had been conjugated with digoxigenin with a DIG oligonucleotide tailing kit (Roche Diagnostics, Mannheim, Germany), overnight at 54 C. The hybridized probes were detected on x-ray film with a DIG luminescence detection kit (Roche Diagnostics) according to the manufacturer’s instruction. The products of PCR specific for GAPDH were subjected to electrophoresis on a 1.5% agarose gel that contained ethidium bromide and photographed under UV light at 254 nm. The bands on x-ray films and agarose gels were recorded as digital images and intensities were determined with NIH image computer software (version 1.57). The intensity of each band specific for AR, 5{alpha}R1, and 5{alpha}R2 was normalized by reference to the band specific for GAPDH. Student’s t test was used for statistical analysis.

Assay of 5{alpha}-reductase activity

Cells were seeded at 1 x 105 cells/well in a 24-well tissue culture dish and were cultured to subconfluence in DMEM supplemented with 10% FBS for 2 days. Then after cells had been washed twice with DMEM, they were incubated with DMEM that contained 20 nM 1{alpha},2{alpha}-3H [N]-testosterone (SA 51 Ci/mmol, NEN Life Science Products, Boston, MA) as substrate for 6 h in a humidified atmosphere of 5% CO2 in air at 37 C, in the presence or absence of MK386, an inhibitor of 5{alpha}R1, or MK906, an inhibitor of 5{alpha}R2, which were kindly provided by Merck & Co., Inc. (Rahway, NJ). The reaction was stopped by addition of four volumes of chloroform-methanol (2/1, vol/vol) that contained 10 µg each of the following nonradioactive carrier steroids that were obtained from Sigma (St. Louis, MO): androstenedione, testosterone, DHT, androstanedione, androstane-3{alpha},17ß-diol, androstane-3ß,17ß-diol and androsterone. The extracted steroids were analyzed by thin-layer chromatography, and the purity of DHT was confirmed by high-performance liquid chromatography. DHT was actually the only 5{alpha}-reduced steroid generated under our conditions.

Results

Expression of genes for AR, 5{alpha}R1, and 5{alpha}R2 in various portions of hair follicles

We compared the levels of expression of GAPDH mRNA semiquantitatively among the five portions of hair follicles from each individual by RT-PCR using serially diluted aliquots of each sample of cDNA as the template. The diluted samples of cDNA that generated similar amounts of products of PCR specific for GAPDH in the case of each of the five portions were used for amplification by PCR of the genes for AR, 5{alpha}R1, and 5{alpha}R2. The levels of expression of AR, 5{alpha}R1, and 5{alpha}R2 mRNAs were assessed in 12 individuals. AR and 5{alpha}R1 mRNAs were expressed in all five portions from almost all individuals at similar respective levels (Figs. 2Go and 3Go). By contrast, 5{alpha}R2 mRNA was expressed in the mesenchymal portions, such as the DP and the upper and lower connective tissue sheaths, but hardly any was expressed in epithelial portions (Fig. 4Go). We also compared the levels of expression of AR, 5{alpha}R1, and 5{alpha}R2 mRNA obtained from mesenchymal portions between balding (four samples) and nonbalding (six samples) scalp. There were no statistically significant differences when cDNA concentrations were adjusted to appropriate levels for comparisons (P > 0.4; data not shown).



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  		Figure 2. Levels of expression of AR mRNA in various portions of hair follicles from the scalp. Products of PCR were blotted to a nylon membrane, allowed to hybridize with a digoxigenin-tailed oligonucleotide probe, and visualized by a chemiluminescence detection method (A). The bands show representative results obtained from the individuals who were subjected to the analysis. The band at the top of the right lane represents a positive control. The numbers refer to patient numbers in Table 1Go. Each point (B) represents the amount of the mRNA expressed in each portion relative to the sum of the values in all five portions. Horizontal bars indicate the average value for each group. MX, Matrix portion; IRS/ORS, inner and outer root sheath; UCTS, upper connective tissue sheath.

 


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  		Figure 3. Levels of expression of 5{alpha}R1 mRNA in various portions of hair follicles from the scalp. See legend to Fig. 2Go for details.

 


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  		Figure 4. Levels of expression of 5{alpha}R2 mRNA in various portions of hair follicles from the scalp. See legend to Fig. 2Go for details.

 
Expression of genes for AR, 5{alpha}R1, and 5{alpha}R2 in cultured DP cells and connective tissue sheath cells

To investigate whether the expression in vivo of AR, 5{alpha}R1, and 5{alpha}R2 by the mesenchymal cells continued in culture, we performed RT-PCR with total RNA extracted from cultured DP cells and connective tissue sheath cells after five or six passages. The AR and 5{alpha}R1 mRNAs were easily amplified (Fig. 5Go), but no obvious products of PCR were detected in the case of 5{alpha}R2 (data not shown in the figure). Again, levels of expression did not differ between cells that originated from balding scalp and those that originated from nonbalding scalp.



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  		Figure 5. Expression of 5{alpha}R1 and AR mRNAs by cultured DP cells and connective tissue sheath cells. A blot of 5{alpha}R2 is omitted because the expression was hardly detected. Numbers refer to patient numbers in Table 1Go. CTS, Connective tissue sheath cells. See legend to Fig. 1Go for details.

 
Effects of inhibitors of types 1 and 2 isozymes on the 5{alpha}-reductase activity of cultured DP cells and connective tissue sheath cells

To confirm that 5{alpha}R1 was also functionally predominant in cultured DP cells and connective tissue sheath cells, we examined the effects of inhibitors specific for each isozyme on 5{alpha}R activity in both kinds of cells obtained from three balding and three nonbalding individuals. MK386, an inhibitor of 5{alpha}R1, decreased the 5{alpha}R activity in a dose-dependent manner, and finasteride, an inhibitor of 5{alpha}R2, had hardly any effect (Fig. 6Go).



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  		Figure 6. The effects of specific inhibitors of 5{alpha}R isozymes on 5{alpha}R activity. The balding samples were obtained from patients 17, 18, and 19 and the nonbalding samples from patients 20, 21, and 22 (Table 1Go). Abscissae and ordinates represent concentrations of inhibitor (nM) and the percentages of control 5{alpha}R activity, respectively. Each point represents an average of two values. MK386, Inhibitor of 5{alpha}R1; MK906, inhibitor of 5{alpha}R2; CTS, connective tissue sheath cells; B, balding sample; NB, nonbalding sample.

 
Discussion

In an attempt to clarify the role of androgen in the development of male-pattern baldness, it is necessary to identify the part of the hair follicle that is a target for androgen because the follicle has a complex structure. The localization of isozymes of 5{alpha}R in the hair follicle is of particular interest because the isozymes are associated with the anabolism or catabolism of androgen in various tissues. At present, the physiological role of 5{alpha}R isozymes in the hair follicle is poorly understood.

Our present study revealed that AR mRNA was expressed in almost all the dissected portions of follicles, suggesting that the expression of AR alone does not necessarily imply responsiveness to androgen. In one earlier study, immunohistochemical staining of AR revealed that AR was restricted to DP cells (19), but another study found that almost all components of hair follicles could be positively stained for AR (20). These conflicting results are probably due to differences in the specificities of the antibodies used. Levels of AR in cultured DP cells from balding scalp have been reported to be slightly higher than those from nonbalding scalp (21). In addition, AR mRNA was found to be expressed at a higher level in cultured DP cells from androgen-responsive hair follicles, such as beard and axillary hairs, than in those from follicles of occipital hairs (22). However, we failed to detect any quantitative differences in terms of the level of expression of AR mRNA in DP cells between balding and nonbalding scalp.

We found that 5{alpha}R1 mRNA was also expressed in almost all portions of the hair follicle, a result that might reflect previous reports that 5{alpha}R1 is the main isozyme in nongenital skin (23, 24, 25). Our finding of the exclusive expression of 5{alpha}R1 and little 5{alpha}R2 in epithelial portions is compatible with previous reports on the expression of transcripts (26) and the characteristics of the 5{alpha}R1 activity (27) in plucked (containing epithelial portions only) and freshly isolated hair follicles (28). Immunohistochemical studies have also shown that 5{alpha}R1 is present in most portions of hair follicles (29, 30). It remains unknown whether 5{alpha}R1 is associated with androgen action in tissues other than sebaceous glands (31) and apocrine glands (32), both of which are androgen target tissues and contain the 5{alpha}R1 isozyme only.

The present study demonstrated that 5{alpha}R2 mRNA was expressed exclusively in mesenchymal portions of follicles. This observation might indicate that 5{alpha}R2 not only in the DP but also in the connective tissue sheath plays a pivotal role in the action of androgen on hair growth as it does in the external genitalia and prostate (9). Indeed, in a coculture system, DP cells from the beard, which have an isozyme with characteristics specific to 5{alpha}R2 (33), stimulate the proliferation of ORS cells in the presence of testosterone (34), whereas DP cells from balding scalp of the stumptailed macaque inhibit the proliferation of cocultured epithelial cells under similar conditions (13). Recently it was shown that 5{alpha}R activity in the hair follicle is concentrated in the DP, although the specific type of isozyme was not reported (35). Other authors have stated that 5{alpha}R2 is the major isozyme in the freshly isolated dermal papillae of occipital hair follicles (36). The results of immunohistochemical localization of 5{alpha}R2 in hair follicles in previous studies are entirely different from our present results: 5{alpha}R2 was localized in very narrow regions of the epithelial portion in two studies (37, 38) and at lower intensity in the ORS in another study (30) but not in dermal papillae.

The ability of mesenchymal cells to express 5{alpha}R2 mRNA was lost in culture, whereas the ability of expressing AR and 5{alpha}R1 mRNAs was retained. The effects of the type-specific inhibitors of 5{alpha}R supported these findings. After many passages, cultured DP cells fail to induce the formation of hair follicles (39). Similarly, cultured fibroblasts from cases of benign prostatic hyperplasia no longer express either type of 5{alpha}R isozyme after several passages (40). To retain patterns of mRNA expression by mesenchymal cells in culture, some factors produced by epithelial cells might be necessary (41). Thus, mesenchymal cells, cultured alone, are not necessarily suitable for studies of the mechanisms of action of androgen in the hair follicle.

We did not find any differences in terms of the expression of AR, 5{alpha}R1 and 5{alpha}R2 mRNAs, or in terms of 5{alpha}R activity between hair follicles from balding and nonbalding scalp. By contrast, in a previous study, hair follicles from balding scalp had higher levels of AR, 5{alpha}R1, and 5{alpha}R2, both in terms of mRNA expression and in terms of enzymatic activity, than those from nonbalding scalp (30). The reasons for these discrepancies remain unknown. The role of 5{alpha}R at a cellular level in the development of male-pattern baldness remains unknown although clinical findings clearly indicate that 5{alpha}R2 is a prerequisite for this condition (9, 10).

Footnotes

1 This work was supported in part by Taisho Pharmaceutical Co., Ltd. (Tokyo, Japan). Back

Received October 26, 2000.

Revised February 1, 2001.

Accepted February 12, 2001.

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