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Endocrinology Vol. 143, No. 11 4389-4396
Copyright © 2002 by The Endocrine Society

ARTICLE

Vitamin D3 Analogs Stimulate Hair Growth in Nude Mice

Vijaya Vegesna1, James O’Kelly1, Milan Uskokovic, Jonathan Said, Nathan Lemp, Takayuki Saitoh, Takayuki Ikezoe, Lise Binderup and H. Phillip Koeffler

Cedars-Sinai Medical Center/University of California Los Angeles School of Medicine (V.V., J.O., J.S., N.L., T.S., T.I., H.P.K.), Los Angeles, California 90048; Hoffman-LaRoche Inc. (M.U.), Nutley, New Jersey 07110; Leo Pharmaceuticals (L.B.), DK-2750 Ballerup, Denmark

Address all correspondence and requests for reprints to: James O’Kelly, Ph.D., Division of Hematology/Oncology, Cedars Sinai Medical Center, University of California Los Angeles School of Medicine, 8700 Beverly Boulevard, Los Angeles, California 90048. E-mail: okellyj{at}cshs.org.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The active form of vitamin D3 can regulate epidermal keratinization by inducing terminal differentiation; and mice lacking the vitamin D receptor display defects leading to postnatal alopecia. These observations implicate the vitamin D3 pathway in regulation of hair growth. We tested the ability of 1,25 dihydroxyvitamin D3 and its synthetic analogs to stimulate hair growth in biege/nude/xid (BNX) nu/nu (nude) mice exhibiting congenital alopecia. Nude mice were treated with different vitamin D3 analogs at doses that we had previously found to be the highest dose without inducing toxicity (hypercalcemia). The mice were monitored for hair growth and were scored according to a defined scale. Skin samples were taken for histological observation of hair follicles and for extraction of RNA and protein. Vitamin D3 analogs dramatically stimulated the hair growth of nude mice, although parental 1,25 dihydroxyvitamin D3 had no effect. Hair growth occurred in a cyclical pattern, accompanied by formation of normal hair follicles and increased expression of certain keratins (Ha7, Ha8, and Hb3). Vitamin D3 analogs seem to act on keratinocytes to initiate hair follicle cycling and stimulate hair growth in mice that otherwise do not grow hair.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
DURING THE COURSE of our investigations into the anticancer properties of vitamin D3 analogs, we routinely used triple immunodeficient beige/nude/xid (BNX) nu/nu (nude) mice to test the abilities of these compounds to prevent tumor growth in vivo. We noticed that the nude mice grew hair when they received certain vitamin D3 analogs.

The nude mice have a germline alteration of the Whn gene (recently called Foxn1) affecting both follicular hair growth and development of the thymus (1, 2). In these mice, the Whn gene has a single nucleotide deletion causing a frame-shift mutation with a premature termination resulting in a nonfunctional protein. The Whn gene, a forkhead transcription factor, is expressed exclusively in epithelial cells in all vertebrate species. The human and murine Whn genes have 85% sequence identity (2). Humans that have the nude phenotype also have congenital alopecia as a result of a nonsense mutation of this gene (3). Transcriptional targets of Whn need to be defined, but they include the keratin genes in the hair follicle. Whn is necessary for the maturation and differentiation of matrix epithelial cells. It is normally expressed in the follicular bulb and outer root sheath of the hair shaft during formation of hair; lack of this gene product in nude mice results in improper keratinization of follicular epithelial cells, leading to defects in the root sheath, cuticle, and cortex, with resultant hair weakness (2, 4, 5). The hair shreds in the follicle, forming dermal cysts (4) that contain keratinized material.

The active form of vitamin D3 is the ligand for a nuclear hormone receptor, the vitamin D3 receptor (VDR). The VDR knockout mice fail to initiate a new hair cycle, exhibiting postnatal alopecia (6). The expression of VDR in the dermal papilla in follicular keratinocytes during the anagen (growth) and catagen (cessation) stages of the hair cycle suggest a role for VDR in progression of the hair cycle (7). Furthermore, treatment of keratinocytes with three vitamin D3 analogs inhibited proliferation and stimulated differentiation (8).

These observations encouraged us to explore the ability of vitamin D3 analogs to stimulate hair growth in nude mice with defects in keratinocytes. A large number of vitamin D3 analogs have been developed that are more potent in their ability to induce differentiation and inhibit proliferation but produce less hypercalcemia than the physiologically active compound, 1,25 dihydroxyvitamin D3 [1,25(OH)2D3] (9). We chose six vitamin D3 analogs that matched these characteristics and examined their ability to cause hair growth in nude mice (10, 11, 12, 13, 14, 15).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Mice
BNX nu/nu male and female mice at 8 wk of age were used in our studies. Animals were maintained in the animal facility at the Cedars-Sinai Medical Center, and experiments were conducted in accordance with institutional guidelines. In one series of experiments, three males were allocated to each of six groups, and each cohort received a different vitamin D3 compound, and a seventh group was composed of untreated control BNX nu/nu. In addition, three male and three female mice received the vitamin D3 analog, EB1089. All of the analogs were injected ip, three times per week, in a vol of 200 µl PBS. For the hair-plucking experiments, hair was plucked from the lower back region of C57 BL/6 mice, and vitamin D3 analogs were administered as described above.

Vitamin D3 compounds
The vitamin D3 compounds (Fig. 1Go) were dissolved in absolute ethanol before determining the molar concentration, as measured by UV absorbency using their molar extinction coefficient at 264 nm. All the analogs were stored in the dark and at -80 C in absolute ethanol as stock solutions of 10-3 M. The last dilution was made in PBS, before administration into mice. The mice were given doses of the vitamin D3 compounds that we had previously found did not produce toxicity, including hypercalcemia. In addition, we monitored the serum calcium levels during treatment.



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  		Figure 1. Physical structure of vitamin D3 compounds used in this study.

 
1,25-(OH)2D3.
1{alpha},25-Dihydroxy-cholecalciferol, the physiologically active form of vitamin D3, was given at 0.0625 µg/mouse; it was made by Hoffman-LaRoche Inc.

Ro 25-9022.
1{alpha},25-(OH)2-16-ene-23-yne-26,27-F6–19-nor-vitamin D3 has six fluorines on the side-chain, unsaturation at C16 and C23, and removal of the C-19 methylene group. It was administered at 0.00125 µg/mouse. This analog was made by Hoffman-LaRoche Inc.

KH 1060.
1{alpha},25-(OH)2-20-epi-22-oxa-24,26,27-trishomo-vitamin D3 has an extension of the side-chain and replacement of C22 carbon with oxygen. It was produced by Leo Pharmaceuticals and given at a dose of 0.0125 µg/mouse.

EB1089.
1{alpha},25-(OH)2-diene-24,26,27-trihomo-vitamin D3 has an altered side-chain featuring 26,27 dimethyl groups, with an insertion of an extra carbon at C-24 (24a) and two trans double bonds at carbons 22,23 and 24,24a. It was produced by Leo Pharmaceuticals and given at 0.05 µg/mouse.

Ro 27-0574.
1{alpha},25(OH)2-23-ene-26,27-hexafluoro-19-nor-20-cyclopyl vitamin D3 contains six fluorines in the side-chain, trans-23,24 double bond and a cyclopropyl group at C20. It was produced by Hoffman-LaRoche Inc. and given at 0.005 µg/mouse.

Ro 27-5646.
1{alpha},25(OH)2-(3-methy-3-hydroxy-butyl)-19-nor-vitamin D3 has two side-chains with removal of C-19 methylene group and was given at 0.01 µg/mouse. It was made by Hoffman-LaRoche Inc.

Ro 26-9114.
1{alpha},25(OH)2-16-ene-19-nor-24-oxo-vitamin D3 contains a double bond at C-16 and a keto group in the side-chain. It was synthesized by Hoffman-LaRoche Inc. and given at a dose of 6 µg/mouse.

Scale for monitoring hair in BNX nu/nu mice
We developed a scale for measuring hair growth in BNX mice (Table 1Go).


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  		Table 1. Scale for monitoring hair in BNX nu/nu mice

 
Histological analysis of hair follicles
Skin samples were obtained after treatment with either vitamin D3 compounds or control diluent. They were fixed for histological analysis in 10% neutral buffered formalin, stained with hematoxylin/eosin, and examined by microscopy.

RNA analysis
Skin samples from mice at their peak score were processed for RNA, made into cDNA, and used in PCR to examine for gene expression of various keratins (10). The primers for the keratin genes are displayed in Table 2Go.


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  		Table 2. Primers for keratin genes

 
Protein analysis
Antisera against keratin proteins were used for Western blotting to establish expression patterns at the protein level (16, 17). One antisera was against type I acidic hair keratin Ha8, which typically shows complex a expression pattern in growing follicles; and the second recognized type II basic hair keratin Hb3.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Nude mice received either vitamin D3 compounds or diluent control at a dose that we previously had found inhibited the clonal proliferation of cancer cells but was not associated with hypercalcemia, which is the major toxicity of vitamin D3 (Table 3Go, Fig. 1Go, and Refs. 10, 11, 12, 13). These mice developed hair as shown in Fig. 2Go. Histological examination confirmed that the vitamin D3 analogs stimulated the formation of hair follicles (Fig. 3Go). Microscopic observation of skin samples, at a peak score of 8 in the vitamin D3 analog treatment groups, showed a fully formed hair follicle; in contrast, no hair follicle or only distorted hair follicles were observed in the control samples.


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  		Table 3. Vitamin D3 compounds: summary of their antiproliferative and calcemic activities

 


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  		Figure 2. Photograph of nude mice. A, The upper mouse received diluant control, and the lower mouse received a vitamin D3 analog, Ro 25-9022, at 0.00125 µg/mouse ip, three times per week. B, Mice received, from left to right: Ro 27-5646 at 0.01 µg/mouse, diluant control, and Ro27–0574 at 0.005 µg/mouse.

 


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  		Figure 3. A, Skin from a control nude mouse with abortive hair follicles and rudimentary pilosebaceous units. Test nude mouse (B) reveals normal hair follicles extending into the sc tissue. This mouse received Ro 25-9022, at 0.00125 µg/mouse ip, three times per week for 36 d (see Fig. 2Go). The sections were stained with hematoxylin and eosin (original magnification, x100).

 
We examined hair growth of nude mice as they received either diluant (control mice), 1,25(OH)2D3, or one of five vitamin D3 analogs. Each group contained three mice. The effect of vitamin D3 analogs on hair growth of nude mice was systematically assessed for each mouse by giving them scores from a scale of 1–10 (Table 1Go), three times per week. The score for hair growth takes into account the thickness and pigmentation of the skin, because this correlates indirectly with induction of anagen, which is the growth phase of the hair cycle. For example, a score of 5 represents skin thickening with heavy pigmentation, which reflects the formation of the hair shaft before the protrusion of the hair above the skin surface. The time to appearance of hair and the hair scores varied from mouse to mouse and among the vitamin D3 analogs (Fig. 4Go).



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  		Figure 4. Effect of vitamin D3 compounds on hair growth in nude mice. Mice were treated with vitamin D3 compounds ip, three times per week, and were scored for hair growth according to the definitions given in Table 1Go. Each panel shows representative experiments. All the mice were males except the females shown in F. *, P < 0.05; #, P < 0.05 for female mice displayed in F.

 
The maximum hair growth score was consistently higher in mice treated with the vitamin D3 analogs than in control mice (Table 4Go). The compounds KH 1060, Ro 27-5646, and EB1089 were the most consistently effective at inducing hair growth. The 1,25(OH)2D3 had little effect on hair growth (Table 4Go, Fig. 4Go). The time to achieve maximal hair growth varied among the vitamin D3 treatment groups. For example, the latency period was, on average, 9 d for mice receiving either Ro 27-0574 or EB1089 (female) groups, whereas it was 18 d for males receiving EB1089, and 21 d for mice receiving KH 1060 (Fig. 4Go). Rapid loss of hair brought the scores to baseline levels within 4 d, even though the vitamin D3 analog treatment was not discontinued. A second cycle of hair growth (peak score, 7–8) occurred in Ro 25-9022-, Ro 27-0574-, and EB1089-treatment groups about 19 d from the first cycle. We also examined the ability of EB1089 to stimulate hair growth in male and female mice. Both had hair stimulation; the first peak of hair growth in females slightly preceded the peak in the males (Fig. 4FGo).


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  		Table 4. Summary of highest hair scores achieved by nude mice treated with vitamin D3 analogs

 
RNA and protein were extracted from the same skin samples, at the highest score of about 8, from the mice treated with EB1089 and Ro 25-9022, and from mice receiving 1,25(OH)2D3 or diluant control. The cDNA was made and amplified for the expression of keratin genes. Expression of keratin mRNA was differentially regulated in skin from vitamin D3 analog-treated animals (Fig. 5Go). The 1,25(OH)2D3 increased the expression of Ha1 mRNA but had no effect on levels of any other of the keratins examined (Fig. 5Go, A and B). Skin from mice receiving either EB1089 or Ro 25-9022 showed significantly increased mRNA expression (P < 0.05) of keratins Ha1, Ha7, Ha8, and Hb3. Expression of Ha4 was not significantly increased by any treatment. Expression of keratins Hb3 and Ha8 was determined at the protein level by Western blot analysis (Fig. 6Go). Consistent with the PCR results, levels of Hb3 and Ha8 were increased in the skin of mice treated with Ro 25-9022 and EB 1089 but not those treated with 1,25(OH)2D3.



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  		Figure 5. A, Effect of vitamin D3 analogs on expression of keratin mRNA in the skin of nude mice. A, RT-PCR analysis of RNA derived from the skin of mice treated with either diluant control, 1,25(OH)2D3, or vitamin D3 analogs. Reverse-transcribed cDNAs were PCR-amplified using primer sets specific for keratins, for 35 cycles, or 18S RNA for 25 cycles. B, Digital quantitation of signals for five keratins as shown in A. Relative keratin expression is determined by normalizing to levels of 18S RNA. Results are presented as percentage of expression, compared with control mice. *, P < 0.05.

 


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  		Figure 6. Effect of vitamin D3 analogs on expression of hair keratin proteins. Western blot was probed sequentially with antisera against Hb3 and Ha8, as well as glyceraldehyde 3-phosphate dehydrogenase (loading control).

 
To address whether the effect of hair growth stimulation by vitamin D3 analogs is specific to nude mice, C57 BL/6 mice were given either Ro 25-9022 or Ro 26-9114, three times per week, after hair regrowth was stimulated by plucking of the hair. Hair scores were taken three times per week using the same scale as described in Table 1Go. No acceleration in the regrowth of hair occurred during treatment with either of the vitamin D3 analogs (Fig. 7Go).



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  		Figure 7. Effect of vitamin D3 analogs on induction of new hair formation after plucking hair from C57 BL/6 mice. C57 BL/6 mice received diluant control, Ro 26-9114, or Ro 25-9022, three times per week, from the day of plucking the hair. Hair scores were taken three times per week. Each symbol represents the mean ± SD from eight mice.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Hair follicles continuously undergo three phases (reviewed in Ref. 18): a growth phase (anagen), an involution stage (catagen), and a resting period (telogen). The molecular signals that control the transition of the follicles between these stages are not fully understood. A variety of hormones have effects on hair growth, including estrogen, GH, and androgens (19, 20). Androgens can promote miniaturization of follicles and shortening of the duration of the anagen stage. In contrast, estrogen can prolong the anagen stage.

The stimulation of hair growth is a so-called holy grail pursued by many scientists, especially those in pharmaceutical companies. Several drugs are on the market that stimulate hair growth, including minoxidil and finasteride (21, 22). Minoxidil prolongs the anagen stage of hair growth and causes follicles at rest to enlarge and grow. It lengthens and enlarges the small vellus hairs and decreases shedding of hair (21). How it mediates these effects is unclear. Finasteride is a 5-{alpha} reductase type 2 inhibitor that decreases serum and cutaneous dihydrotestosterone levels and therefore inhibits androgen-dependent miniaturization of hair follicles (22).

The vitamin D receptor knockout mice are characterized by 1,25(OH)2D3-resistant rickets with hypocalcemia, hypophosphatemia, hyperparathyroidism, rickets, osteomalacia, and alopecia (6, 23, 24). Placing these animals on a high-calcium, phosphorous, and lactose diet can normalize their phenotype, except for the alopecia (23, 25). Furthermore, individuals with vitamin D3-resistant rickets type 2 have a germline inactivating mutation of VDR, with either partial or total alopecia (26). Studies using VDR knockout mice have shown that keratinocytes are the aberrant cells responsible for their hairless phenotype (23, 27). Keratinocytes express Whn, and hair reconstitution assays revealed them to be the defective cell type in the hair development of nude mice (2). Studies have demonstrated that expression of several keratin genes is reduced in nude skin, and that keratin gene transcription could be regulated by Whn (4, 28). In our studies, we showed that treatment of nude mice with vitamin D3 analogs elevated expression of keratins in their skin at the same time as they were growing hair. These observations suggest that vitamin D3 analogs act transiently to normalize keratinocytes of nude mice, which allows production of hair.

Hair plucking induces the initiation of a new anagen phase of the hair follicle. Our experiments using C57 BL/6 mice showed that vitamin D3 analogs had no effect on the reappearance of hair after plucking. This observation suggests that vitamin D3 analogs do not affect the induction of anagen. Vitamin D3 analogs seem to act downstream of Whn, as demonstrated by their ability to increase mRNA expression of the Whn target genes, keratin Ha1, Ha7, Ha8, and Hb3, in the skin of nude mice. The 1,25(OH)2D3 has previously been shown to up-regulate keratin expression during keratinocyte differentiation (29), although this effect was indirect (30). In keratinocytes, Whn is expressed during the early stages of terminal differentiation, where it activates early differentiation markers such as keratin 1 (4, 31). Our observations in nude mice suggest that treatment with vitamin D3 analogs is able to overcome the block in keratinocyte differentiation caused by inactivation of Whn, leading to increased keratin expression and production of visible hair.

A recent study demonstrated that a patient with mutated VDR displayed alopecia indistinguishable from the atrichia caused by mutations in the hairless gene (32). The authors concluded that VDR and the hairless gene may be part of either the same or convergent genetic pathways necessary for normal hair cycling. In hairless mice, the aberrant phenotype is caused by a defect in catagen (33). This raises the possibility that vitamin D3 analogs may be able to regulate the expression of genes that control catagen.

In our experiments, the administration of 1,25(OH)2D3 did not induce hair growth in the nude mice; however, a variety of vitamin D3 analogs did cause hair growth. All of these analogs have been previously shown to have a greater potency to induce differentiation and inhibit proliferation of a variety of cancer-related cell types, both in vitro and in vivo (10, 11, 12, 13, 14, 15) (Table 3Go). Therefore, the likely reason why the vitamin D3 analogs are able to stimulate hair growth in nude mice, whereas 1,25(OH)2D3 cannot, is that they have greater potency in vivo. Each of the analogs is able to bind to VDR (9). Some of the mechanisms that are hypothesized to account for their increased potency include the fact that they have decreased binding to D-binding protein in the serum, which allows more ready access to entering the cell. These analogs may alter the conformation of the VDR, making them more active, or they may prolong the half-life of the activated VDR (34). They could also be modulating the ability of corepressors or coactivators to interact with the ligand-activated VDR (35). Whatever the mechanism may be, these analogs are acting on the hair follicle of the nude mice, probably by stimulating the expression of genes, such as keratins, which are downstream of the defective Whn transcription factor; and these genes are critical to formation of the hair shaft (16, 17, 31). In summary, our results provide strong evidence that vitamin D3 analogs can stimulate the growth of hair in nude mice that normally do not have visible hair.


   Acknowledgments
 


   Footnotes
 
This work was supported, in part, by the Sid and Ann Schwartz family fund, the Horn Trust, and the Parker Hughes Foundation. H.P.K. is the holder of the Mark Goodson Chair in Oncology at Cedars Sinai Medical Center and is a member of the Jonsson Cancer Center.

1 V.V. and J.O. contributed equally and both should be considered first author. Back

Abbreviations: BNX, Beige/nude/xid; 1,25(OH)2D3, 1,25 dihydroxyvitamin D3; VDR, vitamin D3 receptor.

Received January 31, 2002.

Accepted for publication July 24, 2002.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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