Spatial and temporal expression of parathyroid hormone-related protein during wound healing

Parathyroid hormone-related protein is produced by many normal tissues incl uding the skin,where it regulates growth and differentiation of keratinocyt es, To define better the role of parathyroid hormone-related protein in the skin, we investigated the spatial and temporal expression of parathyroid h ormone-related protein and mRNA by immunohistochemistry and in situ hybridi zation during the healing of skin wounds, and the effects of topical admini stration of a parathyroid hormone-related protein agonist [parathyroid horm one-related protein (1-36)] and a parathyroid hormone-related protein antag onist [parathyroid hormone (7-34)] on the healing rate and morphology of th e wounds. Wounds were produced on the back of guinea pigs with a 4 mm punch , and wound sites were collected at different time points during the healin g process. Parathyroid hormone-related protein was expressed in normal skin by all viable keratinocyte layers, hair follicles, and adnexae, Following injury, migratory keratinocytes at wound margins and the newly restored epi dermis expressed increased levels of parathyroid hormone-related protein. T he remodeling phase was associated with progressive restoration of the patt ern of parathyroid hormone-related protein expression in normal epidermis, Granulation tissue myofibroblasts and infiltrating macrophages also express ed parathyroid hormone-related protein. lit vitro studies using THP-I cells (a promonocytic cell line) confirmed that macrophages expressed parathyroi d hormone-related protein, especially after activation. Topical application of parathyroid hormone related protein (1-36) or parathyroid hormone (7-34 ) did not result in significant changes in the healing rate and morphology of the wounds. These findings demonstrated that, in addition to keratinocyt es, myofibroblasts and macrophages also represent sources of parathyroid ho mone-related protein during the healing of skin wounds. Although the data s uggest a role for parathyroid hormone-related protein in the healing of ski n and in the restoration of epidermal homeostasis, parathyroid hormone-rela ted protein does not appear to be required for proper re-epithelialization in response to injury, potentially because of redundancy in epidermal growt h and wound healing, as has been shown for other paracrine and autocrine gr owth factors of the epidermis.