title: Modulation of hair growth with small molecule agonists of the hedgehog signaling pathway.
abstract: The hedgehog (Hh) family of intercellular signaling proteins is intricately linked to the development and patterning of almost every major vertebrate organ system. In the skin, sonic hedgehog (Shh) is required for hair follicle morphogenesis during embryogenesis and for regulating follicular growth and cycling in the adult. We recently described the identification and characterization of synthetic, non-peptidyl small molecule agonists of the Hh pathway. In this study, we examined the ability of a topically applied Hh-agonist to modulate follicular cycling in adult mouse skin. We report that the Hh-agonist can stimulate the transition from the resting (telogen) to the growth (anagen) stage of the hair cycle in adult mouse skin. Hh-agonist-induced hair growth caused no detectable differences in epidermal proliferation, differentiation, or in the endogenous Hh-signaling pathway as measured by Gli1, Shh, Ptc1, and Gli2 gene expression when compared with a normal hair cycle. In addition, we demonstrate that Hh-agonist is active in human scalp in vitro as measured by Gli1 gene expression. These results suggest that the topical application of Hh-agonist could be effective in treating conditions of decreased proliferation and aberrant follicular cycling in the scalp including androgenetic alopecia (pattern hair loss).
authors.affiliation: Curis Inc., Cambridge, Massachusetts, USA. rpaladini@curis.com
authors.forename: Rudolph D
authors.initials: RD
authors.lastname: Paladini
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Saleh
authors.forename: Changgeng
authors.initials: C
authors.lastname: Qian
authors.forename: Guang-Xin
authors.initials: GX
authors.lastname: Xu
authors.forename: Lee L
authors.initials: LL
authors.lastname: Rubin
mesh_terms: D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000078404:Epidermal Cells; D018507:Gene Expression Regulation, Developmental; D006197:Hair / Q000187:drug effects / Q000254:growth & development*; D018859:Hair Follicle / Q000166:cytology / Q000187:drug effects; D053823:Hedgehog Proteins; D006801:Humans; D053550:Keratin-10; D007633:Keratins / Q000235:genetics; D051379:Mice; D009024:Morphogenesis; D015513:Oncogene Proteins / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000819:agonists* / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics; D000071676:Zinc Finger Protein GLI1
chemical_list: D053823:Hedgehog Proteins; C507493:KRT10 protein, human; C507491:Krt10 protein, mouse; D015513:Oncogene Proteins; C509239:SHH protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D053550:Keratin-10; D007633:Keratins; D001973:Bromodeoxyuridine