Is the “Comb Over” Dying? A Mouse Model for Male Pattern Baldness (Androgenic Alopecia)

Androgenic alopecia (AGA) is also known as male pattern baldness, but it affects males and females. In males, AGA results in the commonly observed loss of hair from the top of the head but not on the sides. In women, the result is a general thinning of hair. At least 50% of men will have AGA by their 50th birthday and up to 70% of males will have AGA in later life. It is estimated that 6% of women under age 50 are affected and 30–40% of women aged 70 and over have AGA (1). Hair growth initiates at the base of the hair follicle in the hair bulb (Fig. 1). Cell proliferation occurs in the matrix of the hair bulb, after which the keratinocytes move up into the follicle, differentiating into the layers of the hair and its surrounding sheaths. The process occurs in a repeating cycle initiated with a growth phase (anagen) of 2–7 yr in humans followed by regression (catagen, 2 wk), and a quiescent phase (telogen, 3 months) during which hairs are shed until reentry into anagen to generate a new hair shaft in the existing follicle (2, 3). For individuals with AGA, there is progressive shortening of anagen, resulting in increased shedding of the short-lived hairs, while the follicles produce shorter, finer hairs. The dermal papilla composed of specialized fibroblasts located below the hair bulb is thought to supply the inductive signals needed to control the growth and differentiation of the hair shaft (4, 5). A, Diagrammatic view of a hair follicle during anagen. The dermal papilla at the base of the follicle provides growth signals to hair shaft precursor cells that produce the hair shaft. The bulge region containing stem cells and the sebaceous gland are also shown. B, A model of androgen regulation of the Wnt-β-catenin signaling pathway in dermal papilla cells from an AGA scalp. Wnt signals derived from undifferentiated matrix cells that give rise to the hair shaft precursor cells activate the Frizzled receptor (Frz) that activates disheveled (Dsh), resulting the inactivation of glycogen synthase kinase 3β (GSK-3β) that normally causes the degradation of β-catenin (β-cat). The accumulating β-catenin would normally translocate to the nucleus and cooperate with Tcf/Lef transcription factors to induce gene expression required for hair growth. However, testosterone (T) is efficiently converted to DHT due to elevated levels of 5α-reductase, resulting in high levels of DHT and AR that favor AR-β-cat interactions and the blocking of β-catenin-mediated gene expression. Paradoxically, androgens are major contributors of hair loss for the scalp but stimulate hair growth in other areas. Men castrated before puberty do not develop AGA, but AGA can be triggered in castrated men after injection of testosterone (6). The levels of androgen receptor (AR) are elevated in balding scalp (7, 8) and individuals who lack AR (androgen insensitivity syndrome) do not display AGA (9). The enzyme 5α-reductase that converts testosterone to the more potent dihydrotestosterone (DHT) is also elevated in the balding scalp, and AGA is not observed in men with a congenital deficiency of 5α-reductase (8). Elevated 5α-reductase levels are thought to be the major cause of AGA. In fact, the 5α-reductase inhibitor finasteride can be used to treat AGA, but the use of finasteride is contraindicated in pregnant women because it can cause malformation of the external genitalia of male fetuses (10). The mechanisms by which androgens and AR regulate hair growth have not been fully established. However, it is accepted that androgens can act by at least two pathways to alter cellular physiology. In the classical pathway, androgen binding to the intracellular AR results in a conformational change in AR that frees it from heat shock proteins that sequester AR in the cytoplasm. AR then translocates to the nucleus and binds to specific DNA sequences called androgen response elements that regulate gene expression (11). In the nonclassical pathway, androgen binding to AR in the cytoplasm or at the plasma membrane rapidly (within seconds to minutes) causes the activation of a set of protein kinases including Src, ERK, protein kinase A, Akt, and protein kinase C as well as expression of genes downstream (reviewed in Refs. 12 and 13). Androgens can also increase intracellular levels of inositol-1,4,5-triphosphate (IP3) and diacylglycerol as well as increase calcium influx and calcium-mediated cell signaling (14). In this issue of Endocrinology, Crabtree, Kilbourne, and colleagues (15) report the development of a mouse model that should permit characterization of the molecular mechanisms responsible for AGA. Specifically, transgenic mice were produced that express human AR under the direction of the human keratin 5 promoter. As a result, AR expression in the hair follicles of the transgenic mice is elevated and hair follicles are more sensitive to DHT treatment. After removal of hair by wax stripping, the transgenic mice regrow hair normally under control conditions, but hair regrowth is delayed with daily injections of DHT (5 mg/kg body weight). The authors also use cell culture models (but not dermal papilla cells) to confirm earlier studies showing that after stimulation with DHT, AR interacts with β-catenin (16, 17) and that DHT decreases β-catenin regulated gene expression. Because studies in other cell types have found that androgens and AR can activate β-catenin-mediated gene expression and that β-catenin can induce AR-driven transcription, it will be important to repeat the gene expression studies in dermal papilla cells (16–19). Nevertheless, these results raise the possibility that increased activity of 5α-reductase and increased nuclear AR levels in the hair follicle interfere with the β-catenin signaling pathway resulting in alopecia. The potential for AR blocking β-catenin actions is interesting given the evidence that hair follicle development and cycling is dependent on Wnt-β-catenin signaling (20–22). Wnts are secreted glycoproteins that bind frizzled receptors (Fig. 1). As a result, disheveled proteins block glycogen synthase kinase 3β-mediated phosphorylation and degradation of β-catenin. Thus, in the presence of Wnts, β-catenin accumulates and translocates to the nucleus where it interacts with transcription factors of the T-cell factor/lymphoid enhancer factor (Tcf/Lef) family and stimulates transcription. Wnt3a secreted by the follicular epithelium has been shown to maintain the hair inductive activity of dermal papilla cells (21). Furthermore, anagen requires stabilization and nuclear localization of β-catenin followed by Lef-1-mediated transcription (23–25). The new mouse model will permit further characterization of the mechanism by which androgens alter β-catenin activity. In addition, it should be more practical to screen the thousands of compounds available to pharmaceutical companies as potential hair growth elixirs. Gene and protein expression comparisons in the dermal papilla of AGA model and wild-type cells will be facilitated. The mechanisms by which a number of potential factors known to favor catagen can now be more easily explored including IGF-I, basic fibroblast growth factor, and vascular endothelial growth factor. Agents that promote apoptosis of cells in the hair follicles including TGFβ1, IL-1α, and TNFα can also be investigated (26). The transgenic mice will also permit an investigation into the mechanism of minoxidil (Rogain)-mediated hair restoration. Minoxidil promotes hair growth by increasing the duration of anagen. It causes hair follicles at rest to grow and enlarges suboptimal follicles. The efficacy of minoxidil is variable and temporary, and its mechanism of action is not well understood. It is known that minoxidil is a peripheral vasodilator (K+ channel opener). Interestingly, the K+ATP channel agonist diazoxide nullifies the depolarizing effects of testosterone and blocks calcium influx in response to androgen treatment (14). Is it possible that minoxidil counteracts AGA by inhibiting androgen-mediated calcium influx? Hopefully, the new mouse model will hasten the development of more effective treatments for AGA. Although the advance may not be welcomed by snake oil salesmen and the owners of the Hair Club for Men, devotees of the “comb over” hope that this development results in a new growth industry. Androgenic alopecia; androgen receptor; dihydrotestosterone.