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Different Mechanisms of Syndecan-1 Activation through a Fibroblast-growth-factor-inducible Response Element (FiRE) in Mucosal and Cutaneous Wounds
J. Rautava1,*,
T. Soukka2,
K. Heikinheimo1,
P.J. Miettinen3,
R.-P. Happonen1 and
P. Jaakkola4
1 Department of Oral and Maxillofacial Surgery, Institute of Dentistry, University of Turku, Lemminkäisenkatu 2, FIN-20520 Turku, Finland;
2 Department of Oral Diseases, Turku University Central Hospital, Turku, Finland;
3 Department of Pathology, Haartman Institute and Program for Developmental and Reproductive Biology, Biomedicum Helsinki, University of Helsinki, and Hospital for Children and Adolescents, Helsinki, Finland; and
4 Turku Centre for Biotechnology, University of Turku and Åbo Akademi, Tykistökatu 6B, BioCity, FIN-20520 Turku, Finland;
Correspondence: * corresponding author, jaana.rautava{at}utu.fi
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ABSTRACT
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Syndecan-1 expression is enhanced in cutaneous and mucosal wounds. We have previously demonstrated that wounding-induced syndecan-1 expression in the skin occurs transcriptionally, through a fibroblast-growth-factor-inducible element (FiRE). Here, we show that FiRE is also activated in mucosal wounds. However, both the expression patterns and the activation mechanisms of FiRE are different from those in the skin. In the mucosa in vivo, the activation starts and ends earlier than in cutaneous wounds. FiRE is first detected at around 12 hours in keratinocytes, and the activation declines by the third day after wounding occurs. The activation is seen on the migrating sheet of epithelial mucosa, as in the case of cutaneous wounding. In contrast to the situation in vivo, organ-cultured mucosal wounds exhibit no FiRE activity, while organ-cultured cutaneous wounds show robust activity. Activation in mucosal wounds is enhanced, however, by the application of epidermal growth factor. This suggests that exogenous growth factor activity is required for activation of syndecan-1 in mucosal wounds but not in cutaneous wounds.
Key Words: EGF • epithelium • FiRE • syndecan-1 • wound healing
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INTRODUCTION
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Wound repair can be divided into three phases: inflammation, proliferation, and remodeling. Healing of oral mucosal wounds resembles that of cutaneous wounds in many respects, but there are characteristic features for mucosa, including relatively high tissue turnover in a densely vascularized, saliva-containing environment (Zelles et al., 1995) containing a specific microflora (Moore and Moore, 1994). Oral mucosal wounds heal more rapidly than skin wounds of similar length and depth (Sciubba et al., 1978). Oral wound repair takes place with minimal scarring, and the profile of cytokines and growth factors expressed differs from that of cutaneous wounds. Epidermal growth factor (EGF) is one of the most important growth factors enhancing oral wound healing (Noguchi et al., 1991).
Syndecan-1 is an integral membrane heparan sulfate proteoglycan of the syndecan family (Bernfield et al., 1992). Syndecan-1 has intracellular, transmembrane, and extracellular domains (Mali et al., 1990), and is expressed mainly by epithelial cells at the cell surfaces in suprabasal cell layers (Hayashi et al., 1987; Bernfield et al., 1992). Syndecan-1 binds to extracellular matrix components and may convey information across the cell surface (Elenius et al., 1990). Syndecan-1 is also involved in mediating cell-cell adhesion (Hayashi et al., 1987) and growth-factor binding (Mali et al., 1993; Kato et al., 1998). Recently, syndecan-1 has been found to be associated with various biological functions, including maintenance of alpha-melanocyte-stimulating hormone balance (Reizes et al., 2001), enhancement of virulence of Pseudomonas aeruginosa (Park et al., 2001), and modification of the proteolytic balance in wound healing (Kainulainen et al., 1998).
Syndecan-1 expression is induced during wound healing in adult and neonatal skin. The induction begins within 24 hours of injury, primarily in the proliferating and migrating keratinocytes. The expression returns to baseline after re-epithelialization (Elenius et al., 1991; Gallo et al., 1996). Human fetal skin wounds do not exhibit increased levels of syndecan-1 during healing. This may suggest that syndecan-1 induction in the skin is involved in inflammation and fibrosis, since neither is seen in fetal skin (Gallo et al., 1996). Expression of syndecan-1 is also induced in mucosal wound healing, when the location of the expression switches from the suprabasal cells, where it occurs in intact epithelium, to the basal cells in migrating oral wound epithelium (Oksala et al., 1995).
It has been suggested that syndecan-1 expression is up-regulated by growth factors during cutaneous wound healing, by EGF and keratinocyte growth factor (KGF, also known as FGF-7) in keratinocytes, and by fibroblast growth factor 2 (FGF-2) in fibroblasts (Elenius et al., 1992; Jaakkola et al., 1997). In healing wounds, syndecan-1 regulation is mediated by an FGF-inducible response element, FiRE (Jaakkola et al., 1997, 1998a). This is a 280-bp gene fragment located -10 kb upstream of the syndecan-1 promoter, and is activated in keratinocytes and fibroblasts by the same growth factors that induce syndecan-1 expression in these cells (Jaakkola et al., 1998a). In murine skin-wounding experiments, FiRE was induced in migrating but not in proliferating keratinocytes at the wound edges (Jaakkola et al., 1998b). Activation of FiRE was first seen 24 hours after wounding occurred, and persisted until re-epithelialization was complete, around day 7. Furthermore, within exogenously given adenoviral vectors, FiRE can target gene expression to healing wounds (Jaakkola et al., 2000).
This study was designed to compare the mechanisms of growth-factor-induced wound healing in mucosa and skin and, furthermore, to search for promoter elements that are active during mucosal wound healing. We found that both syndecan-1 and FiRE were activated in mucosal wounds, but the expression patterns and the mechanisms of activation were different from those in cutaneous wounds. Our results suggest that exogenous growth factor activity is necessary in the transcriptional activation of syndecan-1 in mucosal wounds but not in cutaneous wounds.
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MATERIALS & METHODS
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Experimental Animals
Transgenic mice with FiRE in front of a ß-galactosidase reporter gene and EGF-receptor-deficient mice [EGF-R (+/-) or EGF-R (-/-)] were used in the experiments. The breeding of these gene-modified animals has been reported previously (Miettinen et al., 1995; Jaakkola et al., 1998b). All animal experiments were approved by the Ethical Committee of the Medical Faculty, University of Turku, Finland.
Wounding Experiments and Analysis of FiRE Activation
Twenty-two adult FiRE reporter-gene-bearing mice and 12 EGF-R (+/-) mice were used in the wounding experiments. The mice were anesthetized with Hypnorm (Janssen Pharmaceutica, Beerse, Belgium) and Dormicum (Roche Oy, Espoo, Finland). Full-thickness incisional wounds were made on the middle of the tongue. Hair was removed from the backs of animals, and full-thickness wounds were incised on dorsal skin. The wounds were left undisturbed. The animals were killed after 6, 12, and 24 hrs and 2, 3, 5, 7, 10, and 14 days. Control and experimental tissues were excised, fixed in 4% paraformaldehyde for 30 min, washed three times for 30 min, and stained overnight with 1 mg/mL of 5-bromo-4-chloro-3-indolyl-ß-D-galactopyranoside (X-Gal) at room temperature (Behringer et al., 1993). After being stained, tissues were fixed in 4% formalin overnight, dehydrated, and embedded in paraffin. EGF-R (-/-) mice could not be used in the wounding experiments because they died shortly after birth. Only post-natal-day-1 head samples were studied.
Tissue Culture and Analysis of FiRE Activation
Nine adult FiRE mice were killed by carbon dioxide. Wounds were incised on the tongue and on the dorsal skin after removal of hair from the latter. Tongues and skin samples with 1 cm of healthy skin around each wound were cut out by means of scissors. Tissues were cultured in cell culture conditions in DMEM supplemented with 10% fetal bovine serum, penicillin, streptomycin, and L-glutamine. Tissue culture was stopped after 1, 3, and 7 days. EGF, TGF- , or FGF-2 (Peprotech, London, UK) was added to the culture medium (final concentration, 100 ng/mL) after 6 hrs and again after 24 hrs, the final time-point being 48 hrs after each experiment started. This was followed by fixation, X-Gal staining and preparation of histological sections as explained under the heading "Wounding Experiments and Analysis of FiRE Activation".
Immunohistochemical Staining
All paraffin-embedded tissues were cut as 6-µm sections on poly-L-lysine (Sigma Diagnostics, St. Louis, MO, USA) mounted glass slides. Standard techniques were used for hematoxylin-eosin staining. For immunohistochemistry, proliferating cell nuclear antigen PCNA (Novocastra Laboratories Ltd., Newcastle upon Tyne, UK) was stained with a HistomouseTM-SP kit (Zymed Laboratories Inc., San Francisco, CA, USA), and syndecan-1 was stained with a rat monoclonal antibody 281–2 (Jalkanen et al., 1985) by means of a Vectastain Elite ABC kit (Vector, Burlingame, CA, USA), according to the manufacturer’s instructions.
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RESULTS
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Differing Activation of Syndecan-1 Expression in Cutaneous and Mucosal Wounds
Syndecan-1 expression in intact resting skin was restricted to epithelial cells, while immunostaining was seen throughout the basal and spinous cell layers, and granular and keratinized layers remained negative for syndecan-1 (Fig. 1B ). In tongue epithelium, syndecan-1 immunostaining was more restricted, with only the basal cell layer and the most basal cells of the spinous layer being positive for syndecan-1 (Fig. 1A).
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Figure 1. Activation of syndecan-1 during wound healing. (A) Syndecan-1 immunohistochemical staining (brown) of intact skin and (B) tongue mucosa. (C) Induction of syndecan-1 staining is seen 24 hours after wounding occurs in skin and (D) 12 hours after wounding occurs in oral mucosa during the early proliferative phase. (E) Seven days after being wounded, the skin is remodeling, and strong syndecan-1 staining is detected, similar to that in (F) a mucosal wound five days after being wounded. * = wound site.
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During the healing of the skin wounds, syndecan-1 immunostaining increased markedly. Induction first occurred on day one of the incision. It continued throughout the proliferation and remodeling phases, declining after 2 wks, once the wound had re-epithelialized (Figs. 1D , 1F). Immunoreactive syndecan-1 was seen in the hair keratinocyte follicles and also in granulation tissue proximal to the wound site. In general, skin wounds re-epithelialized within approximately 2 wks, tongue wounds in less than a week. After tongue wounding occurred, the proliferation phase was found by PCNA immunostaining to occur between 6 and 48 hrs. After skin wounding occurred, the proliferation phase was detected between 24 and 72 hrs (data not shown). Accordingly, syndecan-1 induction started earlier and declined earlier in mucosal wounds compared with skin wounds. At the beginning of the re-epithelialization phase, syndecan-1 staining was weak in the basal cells and migrating tips of tongue wounds (Fig. 1C). Later, however, syndecan-1 was strongly induced in the epithelium of the wounded area. All cell layers except the granular and keratinized layers were positive for syndecan-1 (Fig. 1E), in contrast to normal tongue epithelium. This pattern of staining continued throughout the remodeling phase, between days 3 and 5. A week after incision, wounded areas had healed, and staining of syndecan-1 had returned to basal levels (data not shown).
Activation of FiRE Precedes the Induction of Syndecan-1
FiRE was activated in mucosal wounds as it was in cutaneous wounds (Fig. 2). In accordance with the faster rate of mucosal wound healing, FiRE activation began and ended earlier in mucosal wounds than in cutaneous wounds. FiRE activation occurred from 6 to 12 hrs after tongue wounding occurred, and from 12 to 24 hrs after dermal wounding occurred. Staining was strongest at 24 hrs after tongue wounding (Fig. 3A) and at 72 hrs after skin wounding (Fig. 3B). Staining started to decline in the mucosal epithelium during the second day after wounding and disappeared completely after three days (Fig. 3C). In contrast, staining started to decline in skin wounds after approximately 7 days (Fig. 3D) and disappeared only after 14 days. In tongue wounds, staining was seen in migrating keratinocytes and in the uppermost cell layers of the epithelium adjacent to the incision site. In skin wounds, however, FiRE activity was seen throughout the epithelium. Apart from the sites of incision, only proximal hair follicle keratinocytes of the epidermis showed staining for FiRE. Proliferating cells in the epidermis (Fig. 3F) and the oral epithelium (Fig. 3E) showed no FiRE activity, as revealed by PCNA and FiRE double-staining.
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Figure 2. The activation of FiRE in vivo in mucosal wounds occurs more rapidly than in cutaneous wounds. (A) In mucosal wounds, FiRE activity detected by X-Gal staining (blue) is most intense at 24 hours after wounding occurs. (B) In cutaneous wounds, FiRE activity is first detected at 24 hours post-wounding. (C) Three days after wounding occurs, FiRE has disappeared from mucosal wounds but (D) is still robust in cutaneous wounds.
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Figure 3. Activation of FiRE during wound healing. (A) FiRE activation by X-Gal staining in a mucosal wound and (B) in a cutaneous wound during the proliferation phase. (C) FiRE is not detected in the mucosal wound during the remodeling phase, but (D) FiRE activity remains in the remodeling cutaneous wound. (E) PCNA immunohistochemical (brown) and FiRE X-Gal (blue) double-staining showing that FiRE is activated in migrating but not proliferating cells in the mucosal wound and (F) in the cutaneous wound. * = wound site.
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FiRE Activation in Organ-cultured Mucosal Wounds is Enhanced by EGF
To study the mechanisms of FiRE activation in mucosal wounds, we used an organ-culture model of wound healing (Jaakkola et al., 1998b). In organ culture, FiRE was activated in cutaneous wounds, whereas epithelial oral wounds either did not exhibit staining or the staining was markedly less than in skin wounds (Figs. 4A–4D). Addition of TGF- or FGF-2 did not activate FiRE in the tongue wounds in vitro. However, supplementation of the cell medium with EGF activated FiRE in wounded tongue tissue, with FiRE activity comparable with that seen in mucosal wounds in vivo (Figs. 4E–4F).
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Figure 4. FiRE activation by X-Gal staining differs in mucosal and cutaneous wounds in organ culture. In organ-cultured mucosal wounds, no activation of FiRE was detected at either 24 hrs (A) or 72 hrs (C). In organ-cultured cutaneous wounds, FiRE activation was clearly detectable at both 24 hrs (B) and 72 hrs (D). (E) The addition of EGF to organ culture of mucosal wounds activated FiRE. (F) Mucosal wound without the addition of EGF. * = wound site.
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Syndecan-1 is Expressed in Mice Lacking EGF Receptors
To study the involvement of EGF further, we analyzed syndecan-1 staining in mucosal and cutaneous epithelia from EGF-R (-/-), EGF-R (+/-), and EGF-R (+/+) mice on day 1 after birth. No difference was found among these newborn mouse lines. Adult EGF-R (+/-) mice were used for wound-healing experiments, and, again, syndecan-1 immunoreactivity was identical between cutaneous and mucosal wounds in EGF-R (+/-) and wild-type mice (data not shown).
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DISCUSSION
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In this study, we examined the activation mechanism of syndecan-1 in mucosal wound healing as compared with cutaneous healing. We show that wounding of both mucosa and skin induced activation of syndecan-1 and FiRE, but that in mucosa and skin, the FiRE activity has distinct expression patterns and mechanisms of activation. Given that the activation of FiRE, a syndecan-1 promoter element, precedes enhanced syndecan-1 expression, and that the activation of FiRE is found in the same cells as syndecan-1 expression, it is likely that FiRE is responsible for the induction of syndecan-1 expression. FiRE and syndecan-1 expression started earlier in tongue mucosa than in skin. The overall period of activation was a quarter of that in skin, perhaps because of the relatively high turnover rate of oral tissues and the dense vasculature, which may provide the needed proteins quickly, as well as biologically active factors in saliva. The shorter period of activation may also reflect the distinct mechanism of wound healing and activation of syndecan-1 in oral mucosa.
Unlike skin wounds, organ-cultured mucosal wounds exhibited no FiRE activity, or markedly less FiRE activity compared with the in vivo situation. Activation of FiRE in the mucosa was enhanced, however, by the addition of EGF. This finding suggests that transcriptional activation of syndecan-1 in mucosal wounds requires exogenous EGF activity. EGF mRNA is in fact detectable in large amounts in skin basal keratinocytes and in hair follicles (Coffey et al., 1987), whereas the tongue apparently does not express sufficient amounts of EGF (Heikinheimo et al., 1993; Chin and Werb, 1997). However, the salivary glands secrete substantial amounts of EGF, and such secretion can contribute to oral wound healing. In vitro, obviously, saliva is absent. Previous studies in fact indicate that EGF plays an important role in the healing of oral soft-tissue wounds (Noguchi et al., 1991). Lack of saliva or lack of EGF in saliva (for example, in patients with diabetes mellitus) delays healing (Oxford et al., 2000). It has also been found that oral surgery results in higher than normal concentrations of EGF in human and animal saliva (Oxford et al., 1999).
In the study reported here, exogenous TGF- did not have the same effect as EGF on FiRE and syndecan-1 expression, suggesting that although EGF and TGF- both bind to and activate EGF-R, the downstream signaling mechanism induced by these growth factors differs significantly. It is worth noticing that different members of the EGF family have been shown to activate different signaling cascades in breast cancer cells and in the developing pancreas (Sweeney et al., 2001; Huotari et al., unpublished observations). Our findings as well as findings in previous studies suggest a need for exogenous EGF, partly because it induces expression of syndecan-1 for proper healing of oral epithelial wounds.
In experiments relating to EGF-R-mediated signaling and syndecan-1 gene induction, no difference in syndecan-1 staining was found between EGF-R (-/-) mice and their wild-type littermates on the first day after birth. This is not surprising, because syndecan-1 expression in resting epithelia is constitutive. No growth-factor activity is required for such housekeeping genes. Normally, EGF, mainly through EGF-R, and KGF, through FGFR-2, activate FiRE expression in epithelial cells (Jaakkola et al., 1998a). In the study reported here, EGF also activated FiRE in mucosal wounds. However, adult EGFR (+/-) mice expressed syndecan-1 in ways similar to those expressed by wild-type animals in both oral and cutaneous wounds. The lower level of EGF-R mRNA in the EGF-R (+/-) mice may still be sufficient to activate the FiRE gene. Unfortunately, we were not able to study syndecan-1 in wounded tissues of EGF-R (-/-) mice, due to the early death of these mice. Finally, syndecan-1 expression and FiRE activation may also be mediated partially through other growth-factor receptors, e.g., heterodimers of EGF-R, with other members of the erbB-family, or FGFR-2 operating via KGF.
FiRE provides a useful tool not only for cutaneous but also for mucosal wound-healing studies. Moreover, although the activation time of FiRE in mucosal wounds is less than that in skin wounds, FiRE may prove to be useful in targeting gene expression to poorly healing mucosal wounds, as has been shown for skin wounds (Jaakkola et al., 2000).
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ACKNOWLEDGMENTS
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The authors are grateful to Mrs. Anni Kieksi, Mrs. Katri Hiillesvuo, and Mr. Jarmo Koskinen for expert technical help. This work was supported by the Finnish Dental Society Apollonia, the Maud Kuistila Memorial Foundation, South-west Finland cancer funds, and the Turku University Foundation.
Received for publication May 20, 2002.
Revision received November 15, 2002.
Accepted for publication January 30, 2003.
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Journal of Dental Research, Vol. 82, No. 5,
382-387 (2003)
DOI: 10.1177/154405910308200511
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ABSTRACT
INTRODUCTION