PTHrP Regulates Epidermal Differentiation in Adult Mice

Abstract

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.

Physical and Functional Interaction between the Vitamin D Receptor and Hairless Corepressor, Two Proteins Required for Hair Cycling

“…PTHrP regulates the rate of keratinocyte differentiation (70), and PTHrP antagonists accelerate anagen and enhance hair growth in mice (71). Thus, PTHrP may be a tonic inhibitor of hair growth.…”

Hormonal Control of Ca Homeostasis in Lower Vertebrates: Considering the Evolution

“…If PTHrP has various functions in mammals, the same must be true in non-mammals PTHrP regulates the differentiation of keratinocytes in the epidermis of mouse (Foley et al, 1998). As mammary glands are not differentiated in the mouse in which the PTHrP gene was knocked out, PTHrP may be involved in the differentiation of the integument and mesenchyme (Wysolmerski et al, 1998a, b).…”

Estrogen modulates mesenchymal-epidermal interactions in the adult nipple

“…However, other factors such as timing of transgene expression or sensitivity of somatic versus lateral plate-derived mesenchymal cells to PTHrP may be involved (Foley et al, 2001). In the adult female mouse, the ectopic expression of PTHrP results in a hairless skin with a thickened epidermis and complex connective tissue consistent with the nipple (Abdalkhani et al, 2002;Foley et al, 2001Foley et al, , 1998. Whether the fibroblasts that underlie the nipple are simply derived from mammary mesenchyme cells remains to be determined.…”