Psoriasis is a benign proliferative disease of keratinocytes of unknown etiology or pathogenesis. It has been estimated that psoriasis affects about 2% of the population in Western countries, 0.1%-0.3% in the Far East, and is rather rare in the black race (Krueger et al. 1984;Yui-Yip, 1984). Although the disease appears to be inherited, its mode of transmission is not known, and more than one genetic locus may be involved (Henseler, 1997). Furthermore, the disease can be triggered or exacerbated by external factors such as trauma, infection, and drugs.
The skin pathology is characterized by acanthosis, angiogenesis of superficial blood vessels, and an inflammatory response. It is not known whether the primary alteration in psoriasis resides in the keratinocytes or is the result of a process of autoimmunity. In this regard there is evidence that an epidermal antigen triggers the appearance of neutrophils, macrophages, and activated T lymphocytes, mostly CD8+ T cells (Chang et al. 1994). This immune response results in the release of various cytokines (interleukins 1, 6, and 8, and tumor necrosis factor 
), which may be responsible for keratinocyte proliferation and angiogenesis (Menssen et al. 1995). Another school of thought suggested that cell adhesion of keratinocytes may be altered in psoriasis and these changes may involve cell-cell and cell-matrix interactions. These studies showed decreased adhesiveness between keratinocytes (Orfanos et al. 1973) and alterations of the basement membrane (BM) at the epidermal–dermal interface (Mondello et al. 1996). In addition, redistribution of 3
1 and 64 integrins from basal to suprabasal keratinocyte layers was noted in both uninvolved and involved skin (Hertle et al. 1992;Pellegrini et al. 1992). It has also been shown that transgenic mice expressing integrins in the suprabasal layer of the epidermis developed a phenotype that closely resembled psoriasis (Carroll et al. 1995).
Matrix metalloproteinases (MMP) are zinc-dependent endopeptidases involved in the remodeling of the extracellular matrix (ECM) and play an important role in morphogenesis, angiogenesis, wound healing, and in certain disorders such as rheumatoid arthritis, tumor invasion, and metastasis (Birkedal-Hansen, 1995). Five subfamilies of MMP have been recognized: collagenases, gelatinases, stromelysins, matrilysins, and membrane-type MMP. These enzymes contain a propeptide, catalytic, and hemopexin (except for matrilysins) domain and are involved in the degradation of collagens, proteoglycans, and various glycoproteins (Birkedal-Hansen, 1995). MMP are secreted as an inactive zymogen (pro-MMP) and their activation (a-MMP) is a prerequisite for function. Stimulation or repression of the synthesis of most pro-MMP is regulated at the transcriptional level by growth factors and cytokines.
In addition, MMP can also be activated by autocatalytic mechanisms and by each other. In vivo activation of pro-MMP involves the removal of the propeptide by serine proteases (trypsin, plasmin, etc.) (Birkedal-Hansen, 1995). Furthermore, post-translational regulation of MMP activity is controlled by tissue inhibitors of MMP (TIMP), and four have been characterized and designated as TIMP-1, TIMP-2, TIMP-3, and TIMP-4 (Gomez et al. 1997). MMP-2 or gelatinase A (72 kDa type IV collagenase) and MMP-9 or gelatinase B (92 kDa type IV collagenase) degrade BMs and have been incriminated in the mechanism of tumor invasion and metastasis. A unique structural feature of MMP-2 and MMP-9 is the presence in their catalytic domain of three tandem repeats of fibronectin type II modules that enable these pro-enzymes and their active forms to bind to gelatin (Collier et al. 1992). MMP-2 binds specifically to TIMP-2 whereas MMP-9 binds to TIMP-1 (Goldberg et al. 1989). MMP-2 has unique structural and functional features that distinguish it from all other MMP. MMP-2 is constitutively expressed in many cells and has a ubiquitous tissue distribution; its promoter lacks a conventional TATA box, AP-1, and PEA-3 site enhancers; and it is not stimulated by serine proteases or tissue plasminogen activator (Birkedal-Hansen, 1995). In addition, MMP-2 responds poorly to growth factors or cytokines, although it can be moderately stimulated by transforming growth factor 1 (TGF-1) (Overall et al. 1991;Salo et al. 1991). Pro-MMP-2 is activated at the cell surface by a cell-membrane MMP known as MT1-MMP (Okada et al. 1990;Sato et al. 1994;Sato & Seiki, 1996).
We are reporting alterations of the BM accompanied by overexpression of MMP-2 and TIMP-2 in the suprabasal layers of psoriatic epidermis, as shown by immunocytochemistry, zymography, western blots, and in situ hybridization.
Materials and methods
Patients
Seventeen patients with widespread plaque psoriasis were selected for this study. There were 13 males and four females, ranging in age from 27 to 73 y old, and duration of disease ranged from 5 to 30 y. Eight patients were in treatment with ultraviolet B, two with psoralen plus ultraviolet A (PUVA), and seven were on no treatment or were only using topical steroids. None of the patients was on methotrexate or retinoids. Skin biopsies under local xylocaine anesthesia were performed from distal uninvolved and involved skin. All patients were provided with informed written consent forms previously approved by the Institutional Review Board at the Mount Sinai Medical Center in New York City. Normal control skin from nonpsoriatic patients was obtained from postsurgical specimens.
Source of antibodies
Antibodies were generous gifts or purchased as stated below. Antibodies against BM components were as follows: affinity purified rabbit polyclonal anticollagen IV (H.K. Kleinman, National Institutes of Health, Bethesda, MD); monoclonal antibodies (MoAb) against the 1 (IV) and 2 (IV) collagen chains (Y. Ninomiya, University Medical School, Okayama, Japan) (Ninomiya et al. 1995); laminin anti-2 chain, MoAb 5H2-F7 (E.S. Engvall, La Jolla Cancer Research Foundation, CA) (Engvall et al. 1990); laminin anti-5 chain, MoAb 4C7 (Gibco, Grand Island, NY); laminin anti-1 chain, MoAb 1921 (Chemicon International, Temecula, CA) (Engvall et al. 1986); laminin anti-
1 chain, MoAb D-18 (Developmental Studies Hybridoma Bank, University of Iowa) (Sanes et al. 1990); EHS-laminin rabbit polyclonal antibody (H.K. Kleinman, National Institutes of Health, Bethesda, MD). Antibodies against metalloproteinases and inhibitors were as follows: MoAb 1346, anti-human MMP-1; MoAb 3308, anti-human MMP-2; MoAb 3309, anti-human MMP-9; and MoAb 3319, anti-MT1-MMP (Chemicon International) (Fujimoto et al. 1993); rabbit polyclonal Ab-45, anti-human MMP-2 (W.G. Stetler-Stevenson, National Institutes of Health, Bethesda, MD) (Monteagudo et al. 1990); rabbit polyclonal 485, anti-human TIMP-2 (H. Birkedal-Hansen, National Institutes of Health, Bethesda, MD); MoAb 3310, anti-human TIMP-2 (Chemicon International) (Fujimoto et al. 1995).
Immunocytochemistry
Skin specimens were frozen in Tissue-Tech OCT embedding compound (Miles Labs, Elkhart, IN). Indirect immunofluorescence microscopy was performed as previously described (Fleischmajer et al. 1993). Specimens were examined using a microscope equipped with epifluorescence illumination or by confocal laser scanning microscopy. Controls consisted of pure mouse IgG or rabbit or mouse serum from nonimmunized animals. In some specimens nuclei were visualized with propidium iodide staining.
Electron microscopy
Skin specimens were immediately immersed in a fixative solution containing 3% glutaraldehyde with 0.2 M sodium cacodylate at pH 7.4. After overnight fixation, the fixative solution was removed and replaced with a phosphate buffer followed by 1% osmium tetroxide buffered with sodium cacodylate. After 1 h, the osmium was replaced with increasing concentrations of ethanol through propylene oxide and placed into embed 812. One micrometer plastic sections were cut, stained with methyl blue and azure II, and observed by light microscopy. Representative areas were chosen for ultra-thin sectioning and observed with a JEM 100CX transmission electron microscope (Jeol, Tokyo, Japan).
Substrate gel electrophoresis (zymography)
Metalloproteinases were detected and characterized by zymography (Nakajima et al. 1995). Uninvolved and involved skin specimens from four patients and two normal controls were extracted in 100 mM Tris-HCl pH 8.0 and 0.1% Triton X-100. Thirty micrograms of Triton soluble protein, as determined by the BCA method (Pierce, Rockford, IL), were loaded on 8% sodium dodecyl sulfate (SDS) polyacrylamide gels that had been copolymerized with 1 mg per ml gelatin. Electrophoresis was performed under nonreducing conditions at 100 V for 2 h at 4°C. Gels were washed once for 30 min in 2.5% Triton X-100 to remove SDS and were then incubated in collagenase buffer (100 mM Tris-HCl pH 8.0, 5 mM CaCl2, 0.02% NaN3) for 40 h at 37°C. Gels were stained with 0.5% Coomassie blue in 30% methanol/10% acetic acid for 30 min at room temperature and de-stained in 30% methanol/10% acetic acid three times for 15 min. The presence of metalloproteinases was indicated by an unstained proteolytic zone in the substrate. Fibroblast conditioned medium, obtained by a 24 h incubation of NIH-3T3 cells with 50 
g per ml ascorbic acid in serum-free Dulbecco's modified Eagle's medium, was used as a positive control for MMP-2.
Western immunoblots
Tissues were extracted with a lysis buffer [50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1% Nonidet P-40, and 5 mM ethylenediamine tetraacetic acid (EDTA)]. Tissue extracts (5 g protein per lane) were run in SDS-polyacrylamide gels (10% for MMP-2 and MT1-MMP and 15% for TIMP-2) and transferred to polyvinylidene fluoride membranes. MMP-2 was detected by incubation with MoAb 3308 or by rabbit polyclonal Ab-45, whereas TIMP-2 was detected with MoAb 3310 or with rabbit polyclonal antibody 485 and MT1-MMP with MoAb 3319. The runs were visualized by an enhanced chemifluorescence detection system (Amersham Pharmacia Biotech, Piscataway, NJ).
In situ hybridization
A human MMP-2, 3 kb cDNA and a human MMP-9, 2.4 kb cDNA were subcloned into Eco R1. Riboprobes were generated by using T3 (antisense) and T7 (sense) RNA polymerase (gift of W. Stetler-Stevenson, National Institutes of Health, Bethesda, MD). The digoxigenin-labeled sense and antisense riboprobes were prepared by in vitro transcription using an RNA labeling kit (Boehringer Mannheim, Indianapolis, IN). Tissues were fixed in 4% paraformaldehyde in phosphate-buffered saline (PBS) (pH 7.2) for 24–48 h, dehydrated, embedded in paraffin, and serially sectioned at 5 m. Sections were placed on triethoxysilane-treated slides, dried overnight at 37°C, and stored at 4°C until used. After deparaffinization, the sections were treated with proteinase K (10 g per ml) for 20 min followed by 0.2 N HCl for 10 min at room temperature. After washings in PBS, sections were acetylated to make mRNA more available for hybridization. Hybridization was performed in hybridization solution containing 50% formamide, 10 mM Tris-HCl, pH 7.6, 200 g per ml tRNA, 1 
Denhardt's solution, 10% dextran sulfate, 600 mM NaCl, 0.25% SDS, and 1 mM EDTA at 50°C for 16 h in a humidified chamber. Slides were washed in 2 sodium citrate/chloride buffer containing 50% formamide and nonhybridized transcripts were digested with 20 g per ml RNase A (Nieto et al. 1996). Detection of the hybridized cRNA was carried out using the Genius Detection System (Boehringer Mannheim), in which the specific transcripts were detected with antidigoxigenin antibody conjugated to alkaline phosphatase. Finally, the slides were immersed in the color-development solution (0.02 mg per ml Nitro Blue Tetrazolium and 0.15 mg per ml 5-bromo-4-chloro-3-indolyl phosphate in 0.1 M NaHCO3). The slides were examined under bright-field microscope.
Results
BM is altered in psoriatic epidermis
Transmission electron microscopy was performed on uninvolved and involved skin from two patients and a normal control. Most of the alterations were noted in the involved skin. There was a marked increase in intercellular spacing between keratinocytes in the basal and suprabasal layers accompanied by a reduction of intercellular bridges, which appeared thin and elongated (Figure 1c). Desmosomes were reduced in numbers and were often found loose in the intercellular spaces. Basal keratinocytes showed numerous vesicles, some opening into the lamina lucida (Figure 1d). The lamina densa revealed gaps and in some areas splitting or reduplication (Figure 1d). The above changes suggested alterations in cell-cell and cell-matrix adhesion in involved psoriatic skin.
Figure 1.
Cell-cell and cell-matrix adhesion is altered in psoriatic skin. Transmission electron microscopy of psoriasis-uninvolved (Ps-U) skin reveals a normal epidermis (A) and a normal epidermo–dermal interface (B). Psoriasis-involved (Ps-I) skin shows widening of keratinocyte intercellular spaces, a reduction in desmosomes, and narrow, elongated intercellular bridges (arrow), suggesting an alteration in cell-cell adhesion (C). Basal keratinocytes reveal numerous vesicles (V) and gaps (arrowheads) of the lamina densa (D). Scale bar: (B-D) 100 nm; (A-C) 1.5 m.
Immunocytochemistry was performed in seven patients (uninvolved and involved skin) and in four normal controls. Indirect immunofluorescence microscopy of the BM was performed with antibodies against 1 (IV) and 2 (IV) collagen chains and against various laminin chains (2, 5, 1, 1). All psoriatic specimens showed alterations of the BM at the epidermo-dermal interface, although the changes were more pronounced in the involved areas. Three abnormalities were noted in the BM at the epidermo–dermal interface, namely (i) large gaps or areas with reduced staining intensity for collagen IV and laminins, (ii) areas of splitting of the BM into several layers, and (iii) marked folding (Figure 2). These changes were more pronounced at the tip of the elongated rete ridges. Superficial capillaries were increased in number and showed dilation or tortuosity, but their BM stained normal with collagen IV and laminin antibodies.
Figure 2.
The BM is altered in psoriatic epidermis. Normal skin control (N) shows linear staining of the BM (arrows) (A). Psoriasis-involved (Ps-I) skin shows gaps, reduced staining intensity (B-D), and excessive folding (C) of the BM. Scale bar: 40 m. V, blood vessels; e, epidermis; d, dermis.
MMP-2 and TIMP-2 are overexpressed in psoriatic epidermis
Uninvolved and involved skin from eight patients with psoriasis and four normal controls were studied by immunohistochemistry with antibodies against MMP-2, TIMP-2, MMP-9, MMP-1, and MT1-MMP. As ultraviolet light may affect the expression of skin MMP (Fisher et al. 1996), three patients included in this series were never previously treated with ultraviolet light, three received ultraviolet B, and two were on PUVA. As there were no differences between the groups, the results will be presented together. MMP-2 was not detected in uninvolved psoriatic skin in seven patients. One patient revealed MMP-2 in the cytoplasm of suprabasal keratinocytes in the rete ridges, however, but not in those localized in the suprapapillary areas. It is noteworthy that suprabasal keratinocytes in involved areas were markedly increased in size compared with those of uninvolved areas (Figure 3a,b). Epidermal expression of MMP-2 was strong in four patients and less pronounced in the other four patients. The dermis did not stain for MMP-2 and MMP-9 in psoriatic skin. MMP-1 was negative in three patients who never received ultraviolet or PUVA therapy (Figure 3c). Normal, control skin was negative for MMP-1, MMP-2, and MMP-9 (Figure 3d). TIMP-2 was present in uninvolved and involved psoriatic skin, but it showed two distinct patterns of distribution. Uninvolved psoriatic skin revealed TIMP-2 mostly at the cell surface of basal keratinocytes facing the ECM (Figure 4a). A similar but less intense staining was noted in the normal controls (not shown). All psoriatic involved specimens revealed TIMP-2 at the cell surface of suprabasal keratinocytes in a linear pattern (Figure 4b). High magnification, by confocal laser microscopy, revealed a distinct, punctate, linear pattern suggesting that TIMP-2 was bound to a cell surface receptor (Figure 4c). As there is evidence that TIMP-2 binds at the cell surface to MT1-MMP (Sato et al. 1994;Strongin et al. 1995;Will et al. 1996), additional staining was performed with a MoAb against MT1-MMP. The results were negative, suggesting that the epitopes for MT1-MMP may be cryptic in the epidermis, as MT1-MMP was clearly demonstrated by western blots (see below).
Figure 3.
There is suprabasal expression of MMP-2 in psoriasis. Immunocytochemistry by confocal laser scanning microscopy. Psoriasis-uninvolved (Ps-U) skin shows MMP-2 in the cytoplasm of several suprabasal keratinocytes. The arrowhead points to the basal cell layer (A). Psoriasis-involved (Ps-I) skin shows intense staining for MMP-2 in most keratinocytes of the suprabasal layer (B). Note that MMP-9 is absent in Ps-I (C). Normal control skin was negative for MMP-2. Scale bar: 10 m.
Figure 4.
TIMP-2 is expressed in suprabasal keratinocytes in psoriasis. Psoriasis-uninvolved (Ps-U) skin shows TIMP-2 in basal keratinocytes, mostly at the epidermo-dermal interface (A). Psoriasis-involved (Ps-I) skin shows TIMP-2 in a distinct pericellular pattern in suprabasal keratinocytes. The arrowhead points to the basal cell layer (B). High magnification by confocal laser scanning microscopy shows TIMP-2 at the cell surface in a punctate, linear pattern (C). Non-reactive control serum (D). Scale bar: (A, B, D) 40 m; (C) 10 m. e, epidermis; d, dermis.
Expression of MMP-2 and TIMP-2 in psoriatic skin as shown by zymography and western blots
Four patients and two normal controls were selected for this study. Three patients (patients 1, 2, and 3) never received ultraviolet or PUVA therapy. Patient 2 was in no treatment (local or systemic) for 2 y. Patients 1 and 3 discontinued all topical therapies for 1 mo, except for occasional use of topical steroids.
Extracts of uninvolved and involved psoriatic skin and two normal control skins were studied by gelatin zymography to determine the presence of pro-MMP-2 and pro-MMP-9, as well as their activated forms. Uninvolved and involved psoriatic skin revealed both pro-MMP-2 and a-MMP-2. On the other hand, pro-MMP-9 was only noted in involved skin (Figure 5). The presence of pro-MMP-9 may be due to local synthesis by keratinocytes or may have been transferred to the epidermis by neutrophils, which are known to store MMP-9 (Birkedal-Hansen, 1995). Normal control skin expressed mostly pro-MMP-2.
Figure 5.
Pro-MMP-2, a-MMP-2, and pro-MMP-9 are present in psoriatic skin. Gelatin zymography of extracts from psoriasis-uninvolved (Ps-U) skin, psoriasis-involved (Ps-I) skin, and a normal skin control (N). CM, conditioned medium from NIH-3T3 cell cultures as a positive control for MMP-2.
Full figure and legend (37K)Western blots with monoclonal and polyclonal antibodies were performed on the above four patients. Pro-MMP-2 and a-MMP-2 were expressed in both uninvolved and involved psoriatic skin, although the signal was more intense in the latter form (Figure 6). Normal control skin was negative or only expressed pro-MMP-2 (Figure 6). TIMP-2 was strongly expressed in uninvolved and involved psoriatic skin, although the signal was more intense in the latter (Figure 6). Normal control skin showed mild expression of TIMP-2. MTI-MMP was also increased in involved psoriatic skin, as shown by western blots (Figure 7).
Figure 6.
MMP-2 and TIMP-2 are increased in psoriatic skin. Western blots for MMP-2 and TIMP-2 in psoriasis-uninvolved (Ps-U) skin, psoriasis-involved (Ps-I) skin, and normal skin controls (N).
Full figure and legend (26K)Figure 7.
MT1-MMP is increased in involved psoriatic skin. Western blots for MT1-MMP in psoriasis-uninvolved (Ps-U) skin, psoriasis-involved (Ps-I) skin, and normal skin control (N). C, culture medium from human endothelial cells of dermal origin as positive control.
Full figure and legend (26K)MMP-2 mRNA is expressed in psoriatic epidermis
Specimens from two patients (uninvolved and involved skin) and from a normal control skin were studied for expression of MMP-2 mRNA by in situ hybridization. Psoriatic uninvolved and involved skin showed strong cytoplasmic signals in the suprabasal layers, as well as in eccrine sweat ducts (Figure 8). Hybridizations with sense MMP-2 mRNAs were essentially negative. Mild signals for MMP-9 mRNA were also noted in involved psoriatic skin (not shown). Normal control skin revealed slight signals for both MMP-2 and MMP-9 mRNAs. Preliminary data showed TIMP-2 mRNA signals only in involved psoriatic skin epidermis whereas the dermis was negative (not shown).
Figure 8.
MMP-2 mRNA is expressed in psoriatic epidermis. In situ hybridization with a human MMP-2, 3 kb cDNA. Psoriasis-uninvolved (Ps-U) skin, psoriasis-involved (Ps-I) skin (patient 2), and normal skin control (N). Control sense RNA. Scale bar: 80 m.
Discussion
The alteration of the BM in psoriatic skin is of considerable interest as these structures play a role in regulating cell adhesion, differentiation, and proliferation. It is also known that MMP-2 and MMP-9 can specifically degrade collagen IV, a major component of the BM. In addition, MMP-2 is also capable of degrading laminins (Yu et al. 1998).
A previous study, performed in early psoriatic lesions, showed expression of MMP-9, mostly in keratinocytes, and MMP-2 in the dermis, whereas TIMP-1 and TIMP-2 were not expressed (Feliciani et al. 1997).
Our study showed overexpression of MMP-2 and TIMP-2 in uninvolved and involved psoriatic skin. The increase in MMP-2 protein and MMP-2 mRNA in uninvolved skin supports the concept that psoriasis is a body-wide disease. Early studies involving transplantation of uninvolved and involved psoriatic skin into athymic mice showed that both were affected, as determined by measuring cell proliferation and plasminogen activator levels (Krueger et al. 1981;Fraki et al. 1982). The overexpression of MMP-2 in psoriatic skin raises the question whether such an increase may be the result of cytokine stimulation by inflammatory cells. This hypothesis appears unlikely, as strong signals for MMP-2 mRNA were also noted in uninvolved skin where inflammatory cells are rarely present. Furthermore, it is known that MMP-2 responds poorly to cytokine stimulation with the exception of TGF-1 (Overall et al. 1991;Salo et al. 1991). It has been shown that fibroblasts and keratinocytes can be moderately stimulated to produce MMP-2 by TGF-1. The presence of TGF-1 in psoriasis is controversial, however, as no expression of MMP-2 mRNA could be demonstrated by in situ hybridization despite an increase shown by immunochemistry (Kane et al. 1990;Shmid et al. 1993). Furthermore, it has recently been shown that TGF-1 stimulation has no effect on MMP-2 mRNA levels, but it increases the stability of the secreted pro-enzyme (Sehgal & Thompson, 1999).
MMP-2 is expressed in the skin during wound healing (Salo et al. 1994) and in certain tumors (Pyke et al. 1992) but usually in the dermis where it plays a role in the remodeling of the ECM. MMP-2 may have additional biologic roles, however, involving cell proliferation, adhesion, and migration (Yu et al. 1998). The role of MMP-2 in psoriatic epidermis remains unknown, although it is noteworthy that cell proliferation and angiogenesis, prominent features in psoriasis, are reduced in MMP-2-deficient mice (Itoh et al. 1998). It has also been shown that ectopic epidermal, suprabasal expression of MMP-1 or collagenase-1 in transgenic mice results in acanthosis and hyperkeratosis (D'Armiento et al. 1995).
The suprabasal expression of TIMP-2 at the cell surface of psoriatic keratinocytes is of considerable interest. TIMP-2 is constitutively expressed in mouse skin during embryogenesis and adult life. In situ hybridization studies, however, showed its mRNA in the dermis and around hair follicles but not in the epidermis (Blavier & DeClerck, 1997). TIMP-2 mRNA was also noted in the stroma of basal cell and epidermoid carcinomas of the skin (Wagner et al. 1996). It is known that TIMP-2, besides acting as a specific inhibitor for MMP-2, has other biologic functions involving regulation of cell proliferation and survival (Gomez et al. 1997;Blavier et al. 1999). The ectopic presence of TIMP-2 at the cell membrane of suprabasal psoriatic keratinocytes is most unusual and raises questions about its role in the activation of pro-MMP-2 as well as its role on cell proliferation in psoriasis. The role of TIMP-2 on cell proliferation has been shown to be paradoxical. Although TIMP-2 inhibits the growth of human melanoma cells (Montgomery et al. 1994), it can stimulate proliferation of a variety of normal and neoplastic cells (Stetler-Stevenson et al. 1992;Nemeth & Goolsby, 1993;Hayakawa et al. 1994). The mechanism by which TIMP-2 activates cell proliferation is not well understood, although there is evidence that it stimulates adenylate cyclase and cAMP-dependent activation of protein kinase A (Corcoran & Stetler-Stevenson, 1995).
The overexpression of MMP-2 and TIMP-2 in psoriatic skin is of considerable interest as it pertains not only to the pathogenesis of this disease but also to their biologic functions in normal skin. The genes for MMP-2 and TIMP-2 have features of housekeeping genes and they are constitutively expressed in many cells during embryogenesis and adult life (Overall et al. 1991;Salo et al. 1994;Hammani et al. 1996;Blavier et al. 1999). The alteration of cell-cell and cell-matrix adhesion in psoriatic epidermis, in association with an increase in the MMP-2-TIMP-2 complex, suggests that these compounds may regulate proteolysis of keratinocyte adhesion molecules and play a role in their transepidermal migration. We hope that future research to define more precisely the biologic roles of MMP-2 and TIMP-2 in psoriasis may enhance our knowledge in keratinocyte biology and also engender new therapeutic approaches for this disabling disease.
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