Metabolic and cellular analysis of alopecia in vitamin D receptor knockout mice.
Targeted ablation of the vitamin D receptor (VDR) results in hypocalcemia, hypophosphatemia, hyperparathyroidism, rickets, osteomalacia, and alopecia--the last a consequence of defective anagen initiation. To investigate whether the markedly elevated levels of 1,25-dihydroxyvitamin D led to the alopecia, we raised VDR-null mice in a ultraviolet light-free environment and fed them chow lacking vitamin D for five generations. Despite undetectable circulating levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, alopecia persisted in the VDR-null mice, demonstrating that the alopecia was not secondary to toxic levels of 1,25-dihydroxyvitamin D interacting with an alternative receptor. Furthermore, alopecia was not seen in control littermates, suggesting that absence of ligand and absence of receptor cause different phenotypes. To identify the cell population responsible for the alopecia, we performed hair-reconstitution assays in nude mice and observed normal hair follicle morphogenesis, regardless of the VDR status of the keratinocytes and dermal papilla cells. However, follicles reconstituted with VDR-null keratinocytes demonstrated a defective response to anagen initiation. Hence, alopecia in the VDR-null mice is due to a defect in epithelial-mesenchymal communication that is required for normal hair cycling. Our results also identify the keratinocyte as the cell of origin of the defect and suggest that this form of alopecia is due to absence of ligand-independent receptor function.
Sakai
Y
Y
Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Kishimoto
J
J
Demay
M B
MB
D000505:Alopecia / Q000209:etiology* / Q000378:metabolism; D000818:Animals; D006197:Hair; D015603:Keratinocytes / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018167:Receptors, Calcitriol / Q000235:genetics / Q000502:physiology*; D014807:Vitamin D / Q000378:metabolism*
D018167:Receptors, Calcitriol; D014807:Vitamin D