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(American Journal of Pathology. 2004;164:2299-2304.)
© 2004 American Society for Investigative Pathology

Animal Model

Plasminogen Mediates the Pathological Effects of Urokinase-Type Plasminogen Activator Overexpression

Isabelle Bolon, Hong-Ming Zhou, Yves Charron, Annelise Wohlwend and Jean-Dominique Vassalli

From the Department of Morphology, University of Geneva Medical School, Geneva, Switzerland


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Increased expression of urokinase-type plasminogen activator (uPA) and its receptor (uPAR) is associated with different pathological conditions. Both uPAR-mediated signaling and plasmin-catalyzed extracellular proteolysis may contribute to pathogenesis. To evaluate the involvement of plasminogen in such circumstances, we have taken advantage of transgenic mouse models in which overexpression of uPA and/or uPAR in enamel epithelium, basal epidermis, and hair follicles leads to a pathological phenotype; uPA transgenic mice have chalky-white incisors and, when uPAR is co-expressed, develop extensive alopecia, epidermal thickening, and subepidermal blisters. We report here that when these transgenic mice were backcrossed into a plasminogen-deficient (Plg–/–) background, the dental and skin phenotypes appeared completely normal. Heterozygous Plg+/– transgenic mice exhibited a haplo-insufficiency, with an intermediate or normal phenotype. These results do not argue in favor of a role for uPAR-mediated signaling in our experimental model; rather, they demonstrate an essential, dose-dependent, requirement for plasminogen in uPA-mediated tissue alterations. They also support the hypothesis that plasminogen could play a part in certain skin diseases.

Plasmin is a tryptic serine protease that can cleave extracellular matrix components both directly and by activating other protease zymogens.1 It is generated from plasminogen, a zymogen abundant in plasma and other extracellular fluids, through limited proteolysis by plasminogen activators. The urokinase-type plasminogen activator (uPA) can be produced by many different cell types, often as a "stress-responsive" protease in tissue destruction and repair. Secreted as a proenzyme (pro-uPA), it can exist either in a soluble form or cell-associated by binding to a specific plasma membrane receptor (uPAR).2 Binding to uPAR increases the efficiency of the uPA/plasmin cascade, by enhancing activation of pro-uPA and by focusing proteolytic activity, for instance, to the leading edge of migrating cells.3-5 The uPA-uPAR interaction can also regulate several intracellular signaling pathways which modulate cell proliferation, differentiation, adhesion, and migration (reviewed in Blasi and Carmeliet, 2002);6 the latter effects appear to be independent of the uPA/plasmin proteolytic cascade and to occur also in the absence of plasminogen.7-11

In view of the different, ie, proteolytic and non-proteolytic functions of uPA and uPAR, it is important to determine which of these operate in specific phenomena in which the enzyme is involved. In particular, in vivo, dysregulated expression of uPA can be highly detrimental, and elucidating the respective contributions of the different uPA functions is necessary to better understand and possibly control pathogenic mechanisms. With this goal, we have previously generated transgenic mice with targeted overexpression of uPA or uPAR in the basal epidermis and the enamel epithelium. The transgene-driven expression of uPA in the enamel epithelium results in abnormal tooth development.12 In the skin, overexpression of either uPA or uPAR alone does not cause detectable alterations in the tissue; in contrast, concomitant expression of both transgenes results in a strikingly altered epidermis.13

To investigate the roles of uPAR signaling and plasmin generation in the phenotypes observed in teeth and skin, we introduced the uPA and uPAR transgenes in a plasminogen-deficient background, by crossing our transgenic mice with plasminogen gene-targeted mice. Our results indicate that the severity of the phenotypes is dependent on the level of plasminogen, and therefore that plasmin-mediated proteolysis, rather that uPAR-mediated signaling, is probably a critical effector in the generation of tissue alterations due to overexpression of uPA and uPAR.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Transgenic Mice

K5-uPA and K5-uPAR transgenic CBA/J mice have been previously characterized.12-13 Plasminogen (Plg) gene-targeted mice,8 on a C57BL/6J background, were kindly provided by Dr. K. Danø (The Finsen Laboratory, Copenhagen, Denmark). For breeding, heterozygous Plg+/– mice were used because of the poor breeding performance of Plg–/– mice. K5-uPA and K5-uPAR transgenic mice were mated to Plg+/– mice. The resulting K5-uPA, Plg+/– were backcrossed to Plg+/– or intercrossed with K5-uPAR, Plg+/– to yield K5-uPA, Plg–/– and K5-uPA/uPAR, Plg–/– mice, respectively.

Genotyping

K5-uPA and K5-uPAR transgenes were identified by PCR using tail tip DNA as previously described.12-13 Genotyping of the mouse plasminogen gene was accomplished by a PCR protocol.14 Briefly, a common primer (PLG INT 3': 5'-TGTGGGCTCTAAAGATGGAACTCC-3') was paired with either the selectable marker (PLG HPRT: 5'-GTGCGAGGCCAGAGGCCACTTGTGTAGCG-3') or a primer from within exon 2 (OligoEx2–5': 5'-GGGGACTCGCTGGATGGCTA-3') to amplify either a 190-bp product from the targeted allele or a 268-bp product from the endogenous allele.

Histological Analysis

Adult mice were killed by cervical dislocation. Back and tail skin were fixed in 4% paraformaldehyde and processed for paraffin sections. Mandibles were digested with proteinase K overnight and incisors were gently extracted and embedded in methylmethacrylate for light microscopy or processed for scanning electron microscopy.

Neonatal mice (day-1) were killed by decapitation. Heads were fixed in 4% paraformaldehyde and embedded in paraffin. They were sectioned sagitally until incisors were seen and 5-µm sections were stained with hematoxylin and eosin.

Assay of uPA Antigen Level

Biopsy-punched (8 mm diameter) pieces of shaved dorsal skin from adult mice were homogeneized in 1 ml ice-cold buffer (100 mmol/L Tris (pH 8.0), 100 mmol/L NaCl, 1 mmol/L EDTA). The homogenates were centrifuged (12,000 x g at 4°C for 10 minutes) and the protein content in the supernatants was determined using a Bradford assay. Five µg of protein per sample were subjected to zymographic analysis for uPA activity.15

Assay of Functional uPAR Level

Triton X-114 (Sigma Chemical Co., St. Louis, MO) was precondensed as described by Bordier.16 Biopsy-punched (8 mm diameter) pieces of shaved dorsal skin from adult mice were homogeneized in 0.5 ml ice-cold buffer: 100 mmol/L Tris (pH 8.0), 100 mmol/L NaCl, 1 mmol/L EDTA, precondensed Triton X-114 (3% final concentration). The homogenates were centrifuged and the protein content in the supernatants was determined using a BCA Protein Assay Kit (Pierce Chemical, Rockford, IL). Five µg of protein per sample were subjected to heat-induced phase separation by a 10-minute incubation at 37°C as described by Bordier.16 The lysates were then centrifuged for 15 seconds at 12,000 x g at room temperature. The upper (aqueous) and the lower (detergent) phases were collected and after equilibration with detergent and salt, respectively, both phases with the total lysate before phase separation were subjected to SDS-PAGE and zymographic analysis for uPA activity15 .


   Results
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 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Plasminogen Deficiency Prevents uPA-Induced Enamel Defects

K5 promoter-driven overexpression of the uPA transgene alters tooth development; transgenic incisors are chalky-white because of the absence of the yellow-pigmented enamel layer that covers the labial side of wild-type rodent incisors.12

To determine whether plasminogen activation by the transgene-encoded uPA is required for the phenotype, we analyzed Plg+/+ (n = 7), Plg+/– (n = 11) and Plg–/– (n = 6) K5-uPA mice. All K5-uPA, Plg+/+ mice had white incisors, whereas incisors of all K5-uPA transgenic mice lacking either one or both Plg allele(s) had a yellow color (Figure 1A) similar to Plg–/– littermate incisors. The surface of the teeth was visualized by scanning electron microscopy. The labial side of K5-uPA, Plg+/+ incisors was covered by sparse plaques of granular material, whereas that of K5-uPA, Plg+/– and K5-uPA, Plg–/– littermate incisors was covered by a regular and smooth layer (Figure 1, B and C) . Analysis of cross sections of non-decalcified incisors embedded in methylmethacrylate confirmed the absence of enamel on the labial side of K5-uPA, Plg+/+ incisors and showed an enamel layer of similar thickness in K5-uPA, Plg+/–, K5-uPA, Plg–/– and wild-type littermate incisors (Figure 2) .



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  		Figure 1. A: Gross appearance of incisors of 3 month-old littermates. B and C: Scanning electron micrographs of the labial surface of incisors. In K5-uPA, Plg+/+ incisors, a few plaques of granular material (arrow) cover the labial surface whereas both K5-uPA, Plg+/– and K5-uPA, Plg–/– incisor surface is uniformly covered by smooth material as is the control Plg–/– incisor surface. Bar, 160 µm in (B) and 20 µm in (C).

 


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  		Figure 2. Labial side of cross-section of non-decalcified incisors. Lack of enamel covering the dentin (asterisks) in K5-uPA, Plg+/+ incisors. Presence of an enamel layer (between two white arrowheads) of equal thickness in K5-uPA, Plg+/–, K5-uPA, Plg–/– and control (wild-type) littermate incisors. Bar, 60 µm.

 
The enamel organ of day-1 littermates was also examined histologically. In K5-uPA, Plg+/+ mice, a disorganized ameloblast layer and deposits of large crystals over the dentin were observed. In contrast, in both K5-uPA, Plg+/– and K5-uPA, Plg–/– enamel organs, the ameloblast epithelium was well organized and a regular layer of enamel covered the dentin (Figure 3) .



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  		Figure 3. Hematoxylin-eosin staining of paraffin sections of enamel organ of 1-day-old mice. In K5-uPA, Plg+/+ mice, ameloblast layer (asterisks) is disorganized and large crystals (arrow) are deposited on the dentin surface. In K5-uPA, Plg +/–, K5-uPA, Plg–/– and control (Plg–/– and wild-type) mice, ameloblasts are well aligned and a regular layer of enamel (between two arrowheads) covers the dentin surface. Bar, 60 µm.

 
Plasminogen Deficiency Prevents the Skin Pathology in K5-uPA/uPAR Bi-Transgenic Mice

By intercrossing K5-uPA, Plg+/– and K5-uPAR, Plg+/– mice we obtained K5-uPA/uPAR bi-transgenics with the three following genotypes: K5uPA/uPAR, Plg+/+ (n = 5), K5-uPA/uPAR, Plg+/– (n = 9), and K5-uPA/uPAR, Plg–/– (n = 5). In agreement with our previous report,13 all K5-uPA/uPAR, Plg+/+ mice progressively developed alopecia and skin blistering (Figure 4A) . In contrast, K5-uPA/uPAR, Plg+/– and K5-uPA/uPAR, Plg–/– mice were hairy (Figure 4A) , even after one year of follow-up. K5-uPA/uPAR, Plg+/+ mice also experienced whisker loss and had a scaly, dull, and naked tail (Figure 4, B and C) . In contrast, K5-uPA/uPAR, Plg–/– mice had a full set of whiskers and a normal hairy and bright tail (Figure 4, B and C) indistinguishable from wild-type littermates. Interestingly, all K5-uPA/uPAR, Plg+/– mice exhibited an intermediate phenotype, with a reduced whisker and tail hair density (Figure 4, B and C) . These three phenotypes were so remarkable that they could be used to predict the Plg genetic background of K5-uPA/uPAR mice with 100% accuracy.



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  		Figure 4. Phenotypes of 5 month-old transgenic mice. A: K5-uPA/uPAR, Plg+/+ mice developed alopecia and blisters (particularly prominent around the neck) whereas the fur of the two other genotypes is similar and comparable to wild-type mice. B and C: K5-uPA/uPAR, Plg+/+ mice are also characterized by the lack of whiskers, sparse tail hair, and a dull aspect of the tail, whereas Plg-deficient double-transgenic mice have full whiskers and a hairy and bright tail. In K5-uPA/uPAR, Plg+/– whiskers and tail hair have an intermediate density.

 
The differences in the phenotypes of K5-uPA/uPAR, Plg+/+, K5-uPA/uPAR, Plg+/–, and K5-uPA/uPAR, Plg–/– mice could be due to differences in the expression of the uPA and uPAR transgenes. Skin protein extracts from adult mice were analyzed by SDS-PAGE and caseinolytic zymography. The level of uPA antigen was similar in all three skin samples (data not shown). To evaluate whether the level of functional uPAR was the same in the three genotypes, skin protein extracts prepared in presence of Triton X-114 were subjected to heat-induced phase separation. The proportion of receptor-bound uPA, which partitions in the detergent phase, versus total uPA was analyzed by caseinolytic zymography; it was equivalent in the three genotypes (data not shown). Thus plasminogen deficiency does not affect expression of functional uPAR

At the histological level, co-expression of uPA and uPAR causes alterations characterized by a thickened back skin epidermis and a flattened tail epidermis with involuted hair follicles.13 To determine whether deficiency in plasminogen modifies these epidermis-specific defects, a microscopic analysis of skin sections was carried out. Hematoxylin and eosin staining of K5-uPA/uPAR, Plg+/+ back skin (Figure 5A) and tail (Figure 5B) revealed the typical epidermis alterations of adult K5-uPA/uPAR mice.13 In contrast, the histology of the above-mentioned sites in K5-uPA/uPAR, Plg–/– was comparable to that in control (Plg–/– and wild-type) mice: the back skin epidermis was thin and the tail epidermis had a wavy structure and normal density of hair follicles. K5-uPA/uPAR, Plg+/– mice showed an intermediate phenotype for both the back skin and tail (Figure 5, A and B) .



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  		Figure 5. Hematoxylin and eosin-stained paraffin sections of adult back skin (A) and tail skin (B). A: Adult back skin epidermis thickness is largely increased in K5-uPA/uPAR, Plg+/+, slightly increased in K5-uPA/uPAR, Plg+/– and comparable to Plg–/– and wild-type adult back skin epidermis in K5-uPA/uPAR, Plg–/– mice. B: In K5-uPA/uPAR, Plg+/+ mice, tail epidermis is flattened and hair follicles are sparse. In K5-uPA/uPAR, Plg+/– tail skin, the epidermis is wavier and hair follicles are more numerous. In Plg-deficient double-transgenic mice, tail skin epidermis folding and the arrangement of hair follicle in clusters are similar to Plg–/– and wild-type tail skin. Bar: 100 µm in (A) and 200 µm in (B).

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
Increased expression of uPA occurs in a variety of pathological circumstances, including infections, inflammatory disorders, and cancer. Determining the part that uPA plays in the altered phenotypes is of obvious interest. To explore this issue, generation of transgenic mice with targeted overexpression of the protein represents a useful approach. We have chosen the skin as a target organ, since it allows easy surveillance of the phenotype and also because certain skin disorders are associated with increased extracellular proteolysis. Our earlier experiments have shown that K5 promoter-controlled overexpression of uPA can cause specific and extensive alterations in the epidermis and its appendages, as well as in the development of teeth. They also demonstrated that the skin, but not the tooth, phenotype requires the concomitant overexpression of the uPAR. In view of the dual role of uPAR, as both binding site that enhances and focuses proteolytic activity and as a signaling receptor modulating cellular responses, it appeared of importance to determine more precisely which function plays the major role in pathogenesis. As a first approach to this question, we explored the effect of a uPAR-binding but catalytically inactive form of uPA; bi-transgenic mice overexpressing both this mutant uPA and the uPAR had a normal tooth and skin phenotype, suggesting a requirement for the enzymatic activity of uPA.12 However, we did not determine whether the mutant uPA expressed in transgenic mice could modulate the signaling activity of the uPAR, nor whether it was the activation of plasminogen or the cleavage of other uPA substrates, such as pro-HGF/SF, fibronectin, or 72-kd procollagenase type IV,17-20 that was required for the lesions to develop.

We have now shown that the pathological phenotypes observed in teeth and skin critically depend on the presence of plasminogen. In the case of the alterations in tooth development, bi-allelic expression of the plasminogen gene is required, suggesting that a threshold level of the zymogen must be present for the transgene-driven uPA to be pathogenic. Interestingly, plasminogen haploinsufficiency has also been described in a physiological tissue remodeling process.21 It is noteworthy that the uPAR is not expressed in the enamel epithelium, and that presence of the uPAR transgene does not modify the tooth phenotype;12 thus, uPAR-mediated enhancement of proteolysis may not occur in teeth, and this may explain why the level of plasminogen must be high for the lesions to develop.

In the skin, where co-expression of transgene-encoded uPA and uPAR results in epidermal thickening, extensive loss of hair follicles and blistering, absence of plasminogen completely prevented the development of the lesions. A partial phenotype was obtained when only one normal plasminogen gene was present, again indicating that the severity of the lesions was dependent on the level of the zymogen. The fact that uPA-induced lesions do develop in the skin even when plasminogen concentration is decreased by mono-allelic deletion of the gene, may be related to the synergistic effect of uPAR overexpression, as well as to the local high concentration of plasminogen in basal epidermis.22,23

Taken together, our results indicate that plasmin generation is critical for uPA-induced pathogenesis in vivo, both in teeth and skin. The presence of increased uPAR levels are also a determinant, at least in the epidermis. The absolute requirement for plasminogen suggests that plasmin-mediated extracellular proteolysis plays a major role, and in this context the fact that uPAR expression enhances plasminogen activation by pro-uPA-secreting cells is probably very relevant. This view does not exclude that uPAR-mediated activation of intracellular signaling cascades, or cleavage by uPA of substrates other than plasminogen, can contribute to pathogenesis; however, if they occur in our experimental model, such events are not sufficient to detectably alter the observed phenotype.

The cutaneous lesions observed in our K5uPA/uPAR bi-transgenic mice have features that are reminiscent of clinical conditions in human patients such as pemphigus and psoriasis.13 Interestingly, overexpression of plasminogen activators has been detected in lesional epidermis of pemphigus and psoriasis patients.24-27 Moreover, in skin organ culture the presence of a high concentration of plasmin(ogen) enhances pemphigus IgG-induced epidermal acantholysis,28 or can, by itself, produce acantholysis.29,30 The present study thus reinforces the notion that plasminogen may be involved in several skin pathologies, where it might be rate-limiting for the development of certain lesions. This suggests that inhibition of (pro-)uPA binding to the uPAR, of plasminogen activation, and of plasmin activity, either individually or in combination, may be useful therapeutic approaches for some skin diseases. In this regard, several reports have shown that inhibition of the plasminogen activator system prevents pemphigus IgG-induced acantholysis in full-thickness skin explants,29,31-34 and treatment of pemphigus patients with an inhibitor of plasminogen conversion to plasmin resulted in the control of the disease with lower corticosteroid doses.34 However, recently Schuh et al35 failed to reproduce these results in a split skin culture system. Moreover, using plasminogen activator-deficient mice, it has been shown that plasminogen activators are not necessary for pemphigus IgG to induce skin blistering and acantholysis in the neonatal mouse model of pemphigus.36 Despite these apparently contradictory reports, we believe that the involvement of plasminogen activation cannot be ruled out in skin blistering diseases. Indeed, in certain experimental in vitro and in vivo models of pemphigus, the non-physiological high levels of one component (plasminogen, uPA/uPAR) or the higher susceptibility to pemphigus-antibody binding (neonatal versus adult epidermis, split skin explant versus full-thickness skin) might overcome the requirement for a combination of autoimmune and proteolytic phenomena for the development of the epidermal lesions, whereas in pemphigus patients, both autoantibodies interfering with desmosomal molecules and extracellular proteases may cooperate to induce loss of cell adhesion and blister formation.


   Acknowledgements
 
We thank Dr. K. Danø for the generous gift of the plasminogen gene-targeted mice. We are grateful to M. Linder, C. Combepine, D. Ben Nasr, and P. Fruleux for excellent technical assistance.


   Footnotes
 
Address reprint requests to Prof. Jean-Dominique Vassalli, Departement de Morphologie, Centre Medical Universitaire, 1 rue Michel Servet, CH-1211 Geneva 4. E-mail: jean-dominique.vassalli{at}medecine.unige.ch

Supported by grant number 3100–055889 from the Fonds National Suisse de la Recherche Scientifique.

Accepted for publication February 9, 2004.


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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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