PTHrP regulates epidermal differentiation in adult mice

Emerging evidence suggests that parathyroid hormone-related peptide (PTHrP) serves as a regulator of the development and/or differentiation of a numbe r of organs, including endochondral bone, the tooth, and the mammary gland. Although disruption of the PTHrP gene by homologous recombination results in a lethal chondrodystrophy, PTHrP-knockout mice that have been rescued by the transgenic replacement of the peptide in cartilage display abnormaliti es in ectodermally derived structures including the skin. At 6-8 wk of age, these rescued PTHrP-knockout mice displayed a markedly thinned epidermis a nd striking hyperkeratosis, hypoplastic sebaceous glands, and a fibrotic de rmis. In contrast, transgenic mice that overexpress PTHrP by virtue of the human keratin-14 promoter displayed a thickened ventral epidermis with mark ed acanthosis and papillomatosis, hyperplastic sebaceous glands, and a cell ular dermis. The absence of PTHrP appeared to result in the reduction of th e basal keratinocyte compartment and premature acquisition of suprabasal an d granular differentiation markers, whereas overexpression of the peptide g enerated reciprocal findings. No difference in the epidermal proliferation rate was found in PTHrP-null skin and although an increase was observed in keratin 14-PTHrP transgenic animals, their epidermis did not express the hy perplasia marker Kb, Finally, the replacement of PTHrP in the basal keratin ocytes of rescued PTHrP-knockout mice under the direction of the keratin 14 promoter reversed the abnormalities seen in PTHrP-null skin. These finding s suggest that PTHrP regulates the rate of keratinocyte differentiation in the skin of adult mice.