Possible mechanism for the stimulation of hair growth by bimatoprost. Bimatoprost stimulates eyelash growth in vivo , human scalp hair growth in organ culture, and mouse pelage hair growth in vivo . In our hypothesis, these effects are due to bimatoprost binding to appropriate receptors on the plasma membrane of cells in the regulatory dermal papilla in the hair bulb (middle panel). This probably stimulates intracellular signaling pathways, which trigger alterations in the gene expression of paracrine signals and their extracellular release. Some of these factors would leave the dermal papilla, crossing the basement membrane, isolating it from the rest of the follicle, to stimulate the coordinated activity of the keratinocytes and melanocytes to produce increased hair growth and pigmentation. Red dots indicate FP and/or prostamide F 2 ␣ receptors, blue arrows indicate direction of movement of paracrine factors. 

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... et al. (37), was extended to include daily observation of follicle morphology and length measurement, modifications that reveal more detail. These allow assessment of any effects on anagen length and provide a more precise rate of growth, since the final hair length can be related to the number of days that the follicle was actually growing. They also enable a more accurate measurement of these increases, since false “growth” caused by upward movement of hairs when follicles enter the catagen-like stage is avoided. The overall alteration in hair length over the experimental period incorpo- rates both the effects on anagen and growth rate. Bimatoprost caused individual isolated scalp hair follicles from 10 different people to stay in anagen longer in organ culture, and about one-third more new hair was synthesized over 9 d with 100 and 1000 nM (Fig. 3). The effect was dose responsive, although raising the concentration to 1000 nM caused no further increases; this would concur with the saturation of a receptor-mediated effect, as reported in other tissues (19, 38, 39). Notably, these results demonstrate that bimatoprost can stimulate growth in human scalp hair follicles, as well as specialized eyelash follicles. Bimatoprost eyedrops also stimulate mouse eyelash growth in vivo (40). Here, its promotion of early anagen in mouse dorsal skin follicles after topical application (Fig. 4) confirms that the bimatoprost response is also not restricted to the specialized eyelash follicles in vivo . This initiation of anagen is a significant aspect of the action from the clinical perspective because of the increased time androgenetic alopecia hair follicles spend in telogen (36) and the need to prompt early entry into anagen to reinitiate hair growth in patients after chemotherapy (41). Minoxidil is also reported to cause this effect (15). The ability to stimulate pelage hair growth by topical application in vivo is also an important asset. Although there are differences between human and mouse skin that prevent direct comparison, topical application is the most appropriate method for alopecia treatments, as the required areas can be targeted, reducing any potential side effects, such as increasing hair growth in inappropriate places, as occurred when minoxidil was initially given orally (15). Because bimatoprost stimulated isolated scalp follicle growth in organ culture, where there is no possibility of involving alterations in blood supply, interactions with other skin tissues, or circulating cells, direct effects on follicles via specific receptors in hair follicle cells are the most likely method of action. The saturation of the effect at receptor- relevant concentrations (Fig. 3) and the ability of the potent prostamide antagonist, AGN 211336, with a pA 2 of 7.6 against the prostamide receptor (20), to block the stimulatory effects of bimatoprost on both hair growth parameters in this dynamic bioassay (Fig. 3) also indicate a receptor-mediated response. The presence of appropriate prostanoid receptors in human scalp hair follicles in vivo (Fig. 6 and Table 1), combined with the organ culture observations, strongly suggest that scalp follicles have the ability to respond with increased growth in vivo . The identifi- cation of genes for the known bimatoprost receptor, FP/altFP4 (30) in scalp hair follicles in vivo (Fig. 6 and Table 1), combined with the prostamide receptor antagonist’s prevention of any effect (Fig. 3 C ), also indicate that bimatoprost acts directly on hair follicles via receptors within them. Studies in FP- deficient mice confirm FP gene expression is essential for bimatoprost effects on intraocular pressure in the eye (42). The location of FP protein (Fig. 5) and the gene expression of FP and splice variants altFP4 and altFP1 (Fig. 6 and Table 1) only in the mesenchyme-derived dermal papilla and CTS is particularly interesting. The dermal papilla determines the type of hair a follicle forms by producing paracrine signals to control other follicular functions (31, 32); the lower follicular CTS can replace this function (28). Reports of prostaglandin-metabolizing enzymes and FP in human scalp cultured dermal papilla cells (43, 44) support this localization in the dermal papilla. The absence of any relevant prostanoid receptors in the bulb keratinocytes, which form the hair or the melanocytes that produce the pigment and the bulge region, the site of epithelial (33) and melanocyte stem cells (34) strongly suggests that the dermal papilla is coordinating follicular responses of increased pigmentation and growth in anagen follicles. Both PGF 2 ␣ and prostamide F 2 ␣ bind to transmem- brane G ␣ q protein-coupled receptors (Fig. 1), which trigger intracellular signaling, resulting in increased intracellular Ca 2 ϩ levels (30). Presumably, this will alter the gene expression of paracrine factors produced by the dermal papilla, which influence the activity of the bulb keratinocytes and melanocytes (see Fig. 7 ). This parallels the mechanism of androgen action in hair follicles (7, 25) and could include increasing production of stem cell factor (SCF), a pigment-stimulating factor reduced in androgenetic alopecia (45) and/or reducing that of TGF- ␤ , an inhibitory factor associated with balding (46). Overall, these experiments demonstrate that the prostaglandin-related glaucoma drug bimatoprost can stimulate growth in non-eyelash hair follicles in mice in vivo and human scalp hair follicles in dynamic organ culture, i.e ., mirroring the stimulation of eyelashes known to occur in vivo . These strong similarities in responses by eyelash and scalp follicles contrast with their differing physiology (23), biological responses to androgens (7), and aging pigmen- tary changes (23). The effects of bimatoprost and its antagonist in hair follicle organ culture suggest that the in vivo action is via direct effects on prostanoid receptors within the follicles themselves, rather than indirect effects involving the vasculature or other surrounding tissues. This is strongly supported by the gene expression of prostanoid receptors, FP, and its splicing variants, notably the altFP4 variant that forms a bimatoprost-sensitive activation site with FP (FP/altFP4; refs. 20, 30), in scalp hair follicles and isolated dermal papillae and CTS in vivo . These results indicate that prostamide receptors and prostamides may be part of a previously unrecognized signaling system within the follicle. Certainly, non- steroidal anti-inflammatory drugs, such as ibuprofen, naproxen, and indomethacin, have been associated with hair loss for many years; these drugs inhibit the enzymes cyclooxygenase-1 and -2, which catalyze early steps in the synthesis of prostaglandins and prostamides (47, 48). Interestingly, the current main treatment for alopecia, minoxidil, increased prostaglandin synthesis in cultured dermal papilla cells (47). Since the development of new treatments for distressing hair growth disorders, such as alopecia and hirsutism, is hampered by our lack of under- standing of hair follicle biology, the specific roles of prostaglandins and prostamides in hair follicles re- quire further analysis. The hair follicle’s regenerative capacity in adults, partially recapitulating embryonic development, with its unique ability to alter the next fully formed state in response to external signals (7) means this system may also have implications for developmental biology (49). Notably, these results demonstrate that bimatoprost offers a novel, and apparently low-risk, approach for treating scalp alopecias, which should reduce the significant problems associated with these distressing ...