Overexpression of bone morphogenetic protein-6 (BMP-6) in the epidermis of transgenic mice: inhibition or stimulation of proliferation depending on the pattern of transgene expression and formation of psoriatic lesions.
Bone morphogenetic protein-6 (BMP-6) belongs to the family of TGF-beta-related growth factors. In the developing epidermis, expression of BMP-6 coincides with the onset of stratification. Expression persists perinatally but declines after day 6 postpartum, although it can still be detected in adult skin by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. We constitutively overexpressed BMP-6 in suprabasal layers of interfollicular epidermis in transgenic mice using a keratin 10 promoter. All mice expressing the transgene developed abnormalities in the skin, indicating an active transgene-derived factor. Depending on the pattern of transgene expression, the effects on proliferation and differentiation were completely opposite. Strong and uniform expression of the BMP-6 transgene resulted in severe repression of cell proliferation in embryonic and perinatal epidermis but had marginal effects on differentiation. Weaker and patchy expression of the transgene evoked strong hyperproliferation and parakeratosis in adult epidermis and severe perturbations of the usual pattern of differentiation. These perturbations included changes in the expression of keratins and integrins. Together with an inflammatory infiltrate both in the dermis and in the epidermis, these aspects present all typical histological and biochemical hallmarks of a human skin disease: psoriasis.
Blessing
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Boehringer Ingelheim Research Group, I. Medical Department, Johannes Gutenberg-University, Mainz, Germany.
Schirmacher
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Kaiser
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D000052:Acanthosis Nigricans / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD / Q000032:analysis; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology*; D002454:Cell Differentiation; D002455:Cell Division; D000078404:Epidermal Cells; D004817:Epidermis / Q000737:chemistry* / Q000196:embryology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006801:Humans; D039503:Integrin alpha6; D053550:Keratin-10; D007633:Keratins / Q000032:analysis / Q000235:genetics; D007642:Keratosis / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009061:Mouth Mucosa / Q000737:chemistry; D011401:Promoter Regions, Genetic / Q000235:genetics; D011565:Psoriasis / Q000209:etiology* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D012867:Skin / Q000737:chemistry / Q000166:cytology / Q000473:pathology*; D013270:Stomach / Q000737:chemistry
D015703:Antigens, CD; C525816:BMP6 protein, human; C525817:Bmp6 protein, mouse; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; D039503:Integrin alpha6; C507493:KRT10 protein, human; C507491:Krt10 protein, mouse; D012333:RNA, Messenger; D053550:Keratin-10; D007633:Keratins