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 number 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 abnormalities in ectodermally derived structures including the skin. At 6-8 wk of age, these rescued PTHrP-knockout mice displayed a markedly thinned epidermis and striking hyperkeratosis, hypoplastic sebaceous glands, and a fibrotic dermis. In contrast, transgenic mice that overexpress PTHrP by virtue of the human keratin-14 promoter displayed a thickened ventral epidermis with marked acanthosis and papillomatosis, hyperplastic sebaceous glands, and a cellular dermis. The absence of PTHrP appeared to result in the reduction of the basal keratinocyte compartment and premature acquisition of suprabasal and granular differentiation markers, whereas overexpression of the peptide generated 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 hyperplasia marker K6. Finally, the replacement of PTHrP in the basal keratinocytes of rescued PTHrP-knockout mice under the direction of the keratin 14 promoter reversed the abnormalities seen in PTHrP-null skin. These findings suggest that PTHrP regulates the rate of keratinocyte differentiation in the skin of adult mice.