title: Basement membrane alterations in psoriasis are accompanied by epidermal overexpression of MMP-2 and its inhibitor TIMP-2.
abstract: Psoriasis is most probably an inherited disease characterized by cell proliferation, angiogenesis, and an inflammatory process. The pathophysiology remains unknown, although an alteration in cell-cell and cell-matrix adhesion versus an autoimmune process has been proposed as the primary defect. Here, we show evidence of a new mechanism involving basement membrane alterations accompanied by keratinocyte overexpression of matrix metalloproteinase (MMP) 2 and tissue inhibitor of MMP-2 (TIMP-2) in both uninvolved and involved psoriatic skin. Immunocytochemistry with antibodies against collagen IV (alpha1, alpha2 chains) and laminins (alpha2, alpha5, beta1, gamma1 chains) revealed gaps, folding, and reduplication of the epidermo-dermal basement membrane. There was overexpression of MMP-2 in the cytoplasm of suprabasal keratinocytes. Gelatin zymography revealed pro-MMP-2 and its activated form, a-MMP-2, in both uninvolved and involved psoriatic skin, whereas pro-MMP-9 was only present in involved skin. TIMP-2 was expressed at the cell surface of psoriatic involved suprabasal keratinocytes whereas it was restricted to basal keratinocytes in uninvolved areas. Western blots showed a marked increase in a-MMP-2 and TIMP-2 in uninvolved and involved psoriatic skin although it was more pronounced in the latter. MT1-MP, known to activate pro-MMP-2, was increased in involved areas. In situ hybridization revealed strong signals of MMP-2 mRNA in both uninvolved and involved psoriatic epidermis. The overexpression of MMP-2 in uninvolved and involved psoriatic epidermis supports the concept that the primary alteration may reside in the keratinocyte. In addition, the presence of the activated form of MMP-2 could be responsible for cell-cell and cell-matrix changes noted in psoriatic epidermis.
authors.affiliation: Department of Dermatology, Mount Sinai Medical Center, New York, NY 10029, USA.
authors.forename: R
authors.initials: R
authors.lastname: Fleischmajer
authors.forename: K
authors.initials: K
authors.lastname: Kuroda
authors.forename: R
authors.initials: R
authors.lastname: Hazan
authors.forename: R E
authors.initials: RE
authors.lastname: Gordon
authors.forename: M G
authors.initials: MG
authors.lastname: Lebwohl
authors.forename: A N
authors.initials: AN
authors.lastname: Sapadin
authors.forename: F
authors.initials: F
authors.lastname: Unda
authors.forename: N
authors.initials: N
authors.lastname: Iehara
authors.forename: Y
authors.initials: Y
authors.lastname: Yamada
mesh_terms: D001485:Basement Membrane / Q000378:metabolism*; D015153:Blotting, Western; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis* / Q000235:genetics; D011565:Psoriasis / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012867:Skin / Q000737:chemistry* / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis*
chemical_list: D012333:RNA, Messenger; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2