Figure 4. Histomorphometric analysis of the hair follicles from the back skin of control and PTH (7-34)-treated mice on the day of maximal macroscopic effects. (A) On the 14th day of treatment oftelogen mice, both the control and treated groups had 13 and 14 mice, respectively. (B) On the 9th day of treatment of spontaneous anagen mice, both the control and treated groups had 14 mice each. (C) On the 11th day of treatment of depilarion-induced anagen mice, the control and treated groups contained 15 mice each. t, values less than 1%; ***, p < 0.001; **. p < 0.01; *, p < 0.05.
if the hair follicle keratinocyte continues to produce PTHrP during its proliferative phase, it, in turn, could exert its antimitotic activity on the dermal papilla, thereby terminating further hair growth and initiating the follicle into catagen and telogen. This effect would render PTHrP an ideal candidate for being one of the long elusive cutaneous chalones (Chase, 1954; Paus et al, 1990, 1991, 1994b, 1994c).
There is additional evidence that PTHrP can alter the hair cycle. Transgenic mice that overexpressed PTHrP displayed a profound disturbance in hair follicle development, particularly in abdominal skin, where a complete lack of hair follicle formation was observed (Wysolmerski et al, 1994). It was also found that whereas the PTHrP agonist PTHrP (1-34) inhibited epidermal proliferation and had no effect on the number or length of hairs of SKH-1 mice, PTH (7-34) had a profound effect on enhancing epidermal proliferation and increasing the number and length of hair shafts (Holick et al, 1994). Because the SKH-1 hairless mouse is not a good model for hair research, however, it is difficult to compare those results with our observations in C57 BL/6 mice. Although it may be possible that PTH (7-34) had a direct effect on melanogenesis, there is no evidence fromin vivo studies to suggest that PTHrP or PTH (7-34) alter melanogenesis (Holick et al, 1994; Wysolmerski et al, 1994). On the background of these data, our observations strongly suggest that PTHrP is a powerful hair cycle modulator involved in anagen termination and telogen maintenance that functions as a molecular brake on anagen.
Our observations demonstrating the dramatic effect of PTH (7—34) on the hair cycle offers a new opportunity to develop PTH analogs for treating disorders of hair growth. Although the PTH (7-34) may have a relatively short circulating half-life (Kukreja et al, 1994), it appears that once it reaches the hair follicle, its biologic half-life is prolonged, resulting in a profound effect on the hair cycle.
We would like to thank David Jackson for his excellent artwork. This work was supported in part by National Institutes of Health Grants DK 43690 and CA 71119-01 (MFH); Endocrine Training Grant DK 07201 (EO); and Deutsche Krebshilfe Wl/94/Pa 1 (RP).
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