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Localization and Regulation of Pregnancy-Associated Plasma Protein A Expression in Healing Human Skin

Endocrine Research Unit, Mayo Clinic and Foundation (B.-K.C., C.A.C.), Rochester, Minnesota 55905; Department of Dermatology, University of Utah Health Sciences Center (K.M.L.), Salt Lake City, Utah 84132; Department of Dermatology, Mayo Clinic and Mayo Foundation (M.R.P.), Rochester, Minnesota 55905; and University of Aarhus (M.T.O., C.O.), DK-8000 Aarhus C, Denmark

Address all correspondence and requests for reprints to: Cheryl A. Conover, Ph.D., Mayo Clinic, 200 First Street SW, 5-194 Joseph, Rochester, Minnesota 55905. E-mail: conover.cheryl{at}mayo.edu.

Pregnancy-associated plasma protein A (PAPP-A) is an IGF-binding protein-4 (IGFBP-4) metalloproteinase that cleaves inhibitory IGFBP-4 to amplify local IGF-I bioavailability in vitro. Thus it has functional implications in injury/repair responses. In this study we determined PAPP-A expression in healing human skin. Wounds were induced with a scalpel on the forearms of three normal subjects and were allowed to heal by first intention. Biopsies obtained on d 0, 2, 8, and 14 were processed for immunohistochemical detection of PAPP-A, IGF-I, and IGFBP-4. In uninjured skin (d 0), strong staining for PAPP-A was present in the epidermis, sweat and sebaceous gland epithelial cells, hair follicles, and blood vessels; no PAPP-A was detected in dermal fibroblasts or with mature collagen bundles. IGF-I localized strongly to epithelial cells of skin glands was weak to moderate in epidermis and blood vessels, and was absent in dermal cells. Weak focal staining for IGFBP-4 was found within uninjured epidermis. During wound healing, PAPP-A expression was induced in dermal granulation tissue within and adjacent to the injury. PAPP-A was present in dermis on d 2 and was increased in intensity and extent on d 8 and 14. PAPP-A expression also increased in the epidermis. PAPP-A expression in cells of granulation tissue colocalized with -smooth actin staining of myofibroblasts and new blood vessels as well as with CD68 staining of macrophages and was associated with the compact, newly synthesized collagen of the healing wound. IGF-I staining was enhanced in the epidermis localized to the area of the incision and in granulation tissue associated with lymphoid cells. IGFBP-4 staining of the epidermis remained unchanged during wound healing, but was induced in the fibroblastic cells of granulation tissue over time. These data demonstrate localized and regulated expression of PAPP-A in human skin and suggest that PAPP-A may play an important role in an integrated IGF system in wound healing and tissue remodeling in vivo.

This work was supported in part by a fellowship grant (to B.-K.C.) from Diagnostic Systems Laboratories.

Abbreviations: IGFBP, IGF-binding protein; IgG, immunoglobulin G; PAPP-A, pregnancy-associated plasma protein A; -SMA, -smooth muscle actin.

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