Induction of bone morphogenetic protein-6 in skin wounds. Delayed reepitheliazation and scar formation in BMP-6 overexpressing transgenic mice

Growth factors of the transforming growth factor-beta superfamily are invol ved in cutaneous wound healing. In this study we analyze the expression of the bone morphogenetic protein-6 (BMP-6) gene, a transforming growth factor -beta related gene, in skin wounds. In normal mouse skin high levels of BMP -6 mRNA and protein are expressed by postmitotic keratinocytes of stratifie d epidermis until day 6 after birth. BMP-6 expression is strongly reduced i n adult epidermis with diminished mitotic activity. After skin injury we fo und large induction of BMP-6-specific RNA and protein in keratinocytes at t he wound edge and keratinocytes of the newly formed epithelium as well as i n fibroblast shaped cells in the wound bed. BMP-6-specific RNA was induced within 24 h after injury, whereas significant upregulation of BMP-6 on the protein level was detected only 2-3 d after injury. Protein was confined to outermost suprabasal epidermal layers, whereas BMP-6-specific RNA was dist ributed throughout all epidermal layers including basal keratinocytes and t he leading edge of the migrating keratinocytes. We also detected high level s of BMP-6-specific RNA and protein in chronic human wounds of different et iology. In contrast to the overall distribution pattern of BMP-6-specific R NA, the protein was not detected in keratinocytes directly bordering the wo und. In order to test the influence of BMP-6 abundance on the progress of w ound healing, we analyzed the wound response of transgenic mice overexpress ing BMP-6 in the epidermis, In these mice, reepitheliazation of skin wounds was significantly delayed, suggesting that strict spatial and temporal reg ulation of BMP-6 expression is necessary not only for formation but also fo r reestablishment of a fully differentiated epidermis.