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1
* Department of Pathology,
Medicine and
Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA
1Correspondence: Box 2603, MSRB, DUMC, Durham, NC 27710, USA. E-mail: green032{at}mc.duke.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, IL-6, and
VEGF production in the wound. Recombinant TG increased vessel length
density (a measure of angiogenesis) when applied topically in rat
dorsal skin flap window chambers. We have established that TG is an
important tissue stabilizing enzyme that is active during wound healing
and can function to promote angiogenesis.—Haroon, Z. A.,
Hettasch, J. M., Lai, T.-S., Dewhirst, M. W., Greenberg,
C. S. Tissue transglutaminase is expressed, active, and directly
involved in rat dermal wound healing and angiogenesis.
Key Words: tissue repair • extracellular matrix • cross-linking • endothelial cells • TGF-ß
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Defects in any phase of wound healing can
contribute to the pathology of many diseases (psoriasis, rheumatoid
arthritis, etc.) and tumor growth (2)
. The tissue
transglutaminase
(TG)2
is a calcium-dependent enzyme that covalently cross-links a wide
variety of extracellular matrix (ECM) proteins, producing a
protease-resistant matrix, and is reported to be expressed at sites of
inflammation (3)
. The TG therefore appears to play a role
in tissue repair and seems to be involved in several phases of wound
healing.
The TG catalyzes the formation of 
-(
-glutamyl) lysine bonds
(isopeptide bond) between peptide-bound glutamine residues and the
primary amine group of various amines (4)
. These
isopeptide bonds are stable and more resistant to proteolytic
degradation than noncovalent linkages. The covalent cross-linking
reaction increases the resistance of proteins to chemical, enzymatic,
and physical disruption (3)
. The list of proteins that are
TG substrates is extensive and includes extracellular adhesive proteins
such as fibronectin (5)
, collagen (6)
,
fibrinogen (7)
, fibrin (8)
, laminin/nidogen
(9)
, osteopontin (10)
, and vitronectin
(11)
, to name a few. Recent data have implicated TG in
several intra- and extracellular processes that are critical for wound
healing including apoptosis (12)
, osteogenesis
(13)
, cellular signaling (14)
, and cell
adhesion (15)
.
Bowness et al. (16
, 17)
reported TG activity was present
at sites of wound healing and that inhibition of TG by putrescine
caused decreased breaking strength and increased solubility of the
repairing wound tissue (18)
. However, the cellular
expression, distribution, and metabolic fate of the TG at sites of
wound healing in relationship to the expression of cytokines and
migration of inflammatory cells were not investigated. The goal of this
study was to identify the distribution of TG antigen, its activity, and
the metabolic fate of TG during wound healing. In addition, the
expression of various cytokines and inflammatory cells associated with
the expression of TG was analyzed. Last, a direct effect of TG on
angiogenesis was studied in an in vivo window chamber model.
These studies and their implications add direct significance to the
role of TG in wound healing and angiogenesis.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Wounds
Fisher 344 female rats from Charles River Laboratories (Raleigh,
N.C.) were anesthetized with intraperitoneal injections of
pentobarbital (40 mg/kg) and ketamine (70 mg/kg), then shaved and
depilated using Nair (Carter-Wallace, New York, N.Y.). Eighteen 5 mm
biopsy punch wounds were made on the dorsal skin. The normal skin
served as unwounded skin controls. Wounds were harvested at days 1
through 9 while animals were anesthetized. Days 0, 1, 3, 5, 7, and 9
postwounding were used in Western blots; days 0, 1, 2, 4, 6, and 8 were
used for immunohistochemistry. Two rats were killed for each time point
by intravenous pentobarbital overdose and the experiments were done in
triplicate. Tissues were either snap-frozen in liquid nitrogen for
Western blots and kept at -80°C or fixed in 10% neutral buffered
formalin for paraffin embedding for immunohistochemistry.
Window chambers
Dorsal skin flap window chambers were used as described by
Papenfuss et al. (19)
. Briefly, Fisher 344 rats were
anesthetized and the skin over the back was depilated and surgically
prepared. The skin flap was pulled dorsally away from the back. Two
opposing 1 cm diameter windows were created on each side of the flap by
surgically resecting the epidermis. One to two fascial planes were
left, which contained a few preformed vessels. The resultant
subcutaneous (s.c.) window was protected by glass coverslips and held
away from the body of the animal by an anodized aluminum
superstructure. This wounded tissue window created a visual field
through which the process of wound healing could be observed
noninvasively. Recombinant human TG (500 µl of 40 µg/ml or 40 µM)
(20)
was applied topically on the day of surgery and on
days 1 and 2 postsurgery. Normal saline was used as a control. Rats
were killed at day 10. Intravital microscopy was used to document the
level of neovascularization at days 1 and 10. Quantitation of
angiogenesis was provided by measuring vessel length density
(21)
.
Immunohistochemistry
Immunohistochemistry was carried out using procedures described
by Hsu et al. (22)
. Briefly, paraffin embedded tissues
were sectioned (5 µ) and antigen retrieval was performed using
citrate buffer from Biogenex (San Ramon, Calif.). Tissues were treated
with primary antibody against tissue transglutaminase (TG100 and CUB
7402, 1:10, nonreactive to factor XIIIa: both monoclonals were epitope
mapped to a region between 447–538 amino acids; unpublished results),
vascular endothelial growth factor (VEGF 3; 1:100; Neomarkers, Fremont,
Calif.), ED1-macrophage marker (MCA341, 1:100; Serotec, Oxford, U.K.),
isopeptide (814 MAM, 1:75; CovalAB, Oullins, France) (23, 24),
panspecific tumor growth factor ß (TGF-ß: AB-100-NA, 1:100, which
recognizes the active forms of TGF-ß1, 2, and 5), rat anti-tumor
necrosis factor (anti-TNF-: AB-510-NA, 1:100; R&D, Minneapolis,
Minn.), interleukin 6 (R-19, 1:100; Santa Cruz, Santa Cruz, Calif.),
and mast cell tryptase (M7052, 1:100; DAKO, Carpinteria, Calif.).
Secondary and tertiary antibodies were provided in a kit (314KLD) by
Innovex (Richmond, Calif.) and the location of the reaction was
visualized with 3, 3'-diaminobenzidine tetrahydrochloride Sigma (St.
Louis, Mo.). Slides were counterstained with hematoxylin and mounted
with coverslips. Controls for the immunohistochemistry were treated
with normal mouse serum (NMUS) or mouse immunoglobulin G (IgG) (TG100,
CUB 7402, 814 MAM, M7052, VEGF 3, and MCA 341), rabbit IgG (AB-100-NA),
and goat IgG (IL-6, AB-510-NA) and were negative in any reactivity.
Masson's trichrome and hematoxylin and eosin were carried out as
described by Sheehan and Hrapchak (25)
.
Western blot
Wounds from days 0, 1, 3, 5, 7, and 9 were homogenized in
2 ml cold lysis buffer containing the proteolytic inhibitor mixture
(#1697498; Boehringer Mannheim, Mannheim, Germany), followed by
sonification. The blots were performed with four different wound sets.
They were then centrifuged, and supernatant was removed and protein
content was determined using Bio-Rad. Gel electrophoresis of the
extracted tissue samples (50 µg/ml) was performed on an 8.5%
polyacrylamide gel using the buffer system of Laemmeli. After
electrophoresis, the proteins were transferred to nitrocellulose (0.2
µM). When the transfer was complete, the nitrocellulose membrane was
blocked for 1 h with 5% nonfat milk dissolved in 20 mM Tris-HCl,
pH 7.4, 150 mM NaCl, 0.5% Tween 20. The TG antigen was detected by
incubation for 1 h using a monoclonal antibody for TG (TG 100, CUB
7402; Neomarkers) diluted 1:1000, followed by incubation for 1 h
with sheep anti-mouse IgG conjugated to horseradish peroxidase. The TG
antigen was visualized using chemiluminescence reagents (ECL, Amersham,
Arlington Heights, Ill.) and a 30 s exposure to autoradiography
film. The amount of protein on the blot was estimated with a
densitometer. The data in Fig. 5A
show one sample blot, and
Fig. 5B
contains the cumulative data for the four blots in a
graphical presentation.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A), provisional matrix with inflammatory cells (Fig. 2
A) and dilated blood vessels could be observed underneath a
newly formed epithelial layer. Re-epithelialization was completed by
day 2 postwounding. Maturation of granulation tissue was detected by
day 4 (Fig. 1B
) and characterized by the presence of new
blood vessels, inflammatory cells (Fig. 2B, C
), and collagen
fibers organized into a dense connective tissue. Skeletal muscle cells
that had formed a boundary between the normal and wounded tissue at
earlier time points now moved to the base of the wound and closed the
gap created by the injury (Fig. 1B
). By day 6 (Fig. 1C
), granulation tissue started to contract and increased in
density. At day 8 (Fig. 1D
) the healing was in its final
stages, with remnants of granulation tissue left at the base of the
wound. The injury site was filled with dense collagen tissue, with very
few blood vessels. The widely recognized three stages of wound healing
(1)
and their time course in our model of healing are
depicted at the bottom of Fig. 1
.
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Expression and localization of TG
The normal rat skin consistently expressed TG antigen in the
blood vessels that reside in the dermis and s.c. tissue (Fig. 3
A). Some sebaceous glands and basal keratinocytes also showed
expression, but in a sporadic fashion. The TG antigen was detected in
the new blood vessels, which invaded the provisional fibrin matrix and
the dilated blood vessels at day 1 postinjury (Fig. 3B-D
).
The TG antigen staining was particularly intense in macrophages
adjacent to the re-epithelialization border and in the provisional
matrix (Fig. 3B, C
). Mast cells (Fig. 2D
) were
present in highest density on day 1 postwounding and exhibited TG
expression. The keratinocytes involved in re-epithelialization
expressed TG antigen (Fig. 3B
). TG reactive skeletal muscle
cells, macrophages, and blood vessels formed a distinct boundary
between the normal and injured tissue (Fig. 3C
). TG was also
detected in the provisional fibrin matrix (Fig. 3D
). By day
2, re-epithelialization was complete and TG expression was reduced in
the epithelial layer and limited to the dermoepidermal junction. The
provisional fibrin matrix was slowly replaced by granulation tissue by
day 2, and the wound began to accumulate collagen and TG antigen
reactivity. TG immunoreactivity in the collagen also increased as the
number of endothelial cells, macrophages, and skeletal muscle cells
increased in the wound.
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The TG antigen (Fig. 3E
) and macrophage (Fig. 2B
)
staining was absent from the keratinocyte layer at day 4. Macrophages,
endothelial cells in the neovessels, and more mature vessels continued
to stain for the TG antigen (Fig. 3E
). The TG reactive
skeletal muscle cells started to move underneath the wounded tissue to
bridge the gap created by injury (Fig. 3E
). TG was still
present in the granulation tissue matrix at day 4 (Fig. 3F
).
As the granulation tissue continued to contract and the tissue was
further remodeled (day 6), the highly reactive TG at the edge of the
wound vanished and TG staining became localized to the blood vessels
and base of the wound (Fig. 3G
). By day 8, the early
granulation tissue was replaced with a dense collagen-rich scar. The TG
antigen was predominantly expressed in blood vessels, skeletal muscles,
and macrophages at the base of the wound (Fig. 3H
). A few
remaining vessels in the scar tissue also exhibited TG staining (Fig. 3H
).
Localization of TG activity
The isopeptide bond created by TG cross-linking was detected
surrounding blood vessels, newly generating epithelial layer, and
fibrin by day 1 of wounding (Fig. 3I
). The intensity of
immunoreactivity of the isopeptide bond increased within the ECM of the
granulation tissue, basement membrane of blood vessels, and along the
epithelial region at day 4 (Fig. 3J
). In contrast to the
reduction of staining for TG and the redistribution of the TG antigen
to the base of the wound, the isopeptide bond antigen continued to be
detectable, but at a reduced level, during the formation of the dense
scar tissue at day 8.
Expression of cytokines (TGF-ß, TNF-, IL-6, and VEGF)
TGF-ß was maximally expressed at the wound surface, granulation
tissue, and wound border over the entire time course examined
(Fig. 4
A). The intensity of staining was greatest in regions where
TG antigen reactivity was the highest. The one exception to this
finding was in the mature epithelial layer at day 4, where TGF-ß
antigen was expressed but TG was absent.
|
Interleukin 6 (IL-6) stained intensely in the skeletal muscle
cells of the dermis throughout the study (Fig. 4B
), with
less intense staining in the macrophages, fibroblasts, and endothelial
cells during the early wound healing (days 1–4). IL-6 coexpressed with
TG in the skeletal muscle cells at all time points examined. TNF-
stained predominantly macrophages in the wounded tissue and coexpressed
with TG in those cells throughout the healing process (Fig. 4C
). Endothelial cells and skeletal muscle cells also
exhibited partial expression of this cytokine.
The endothelial cells and macrophages expressed VEGF antigen at day 1
postwounding (Fig. 4D
), which correlated with TG expression.
VEGF expression in endothelial cells and macrophages decreased in
intensity even though TG continued to be expressed at high levels at
day 4. By day 8, TG and VEGF coexpressed in remnant blood vessels in
the scar tissue.
A summary of the immunohistochemical data is provided in Table 1
.
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Western blot analysis of TG antigen in wounded tissue
Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and
quantitative immunoblotting demonstrated that the total TG antigen
increased from four- to fivefold by day 3 (Fig. 5
A, B). Quantitative analysis of the antigen (n=4)
revealed that more than 95% of the protein was proteolytically
degraded to 55, 50, and 20 kDa fragments by day 1 postwounding. The
extent of proteolysis and the amount of TG antigen reached maximum by
day 3, after which the full-length TG antigen was detected. The total
TG antigen levels returned to baseline values by day 9. However, the
amount of intact protein was still considerably reduced compared with
the control skin tissue.
Effect of recombinant TG on angiogenic response in rat dorsal skin
flap chamber
To determine what effect the active TG had on dermal wound
healing, we used the rat dorsal skin flap window chamber to administer
full-length recombinant TG and measure its effects on angiogenesis.
When recombinant TG was applied to fascia in the rat dorsal skin flap
window chambers, a significant doubling in the vessel length density
was measured at day 10 compared to controls (P=0.05)
(Fig. 6
).
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|
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. The TG could be exerting its effects during wound healing either in
1) response to injury cytokines, 2) stabilization
of provisional fibrin matrix, 3) migration of endothelial
and inflammatory cells, and/or 4) remodeling of the
granulation tissue through apoptosis and cross-linking.
|
The finding that both TG expression and activity were increased very
early during wound healing demonstrated that the TG gene was activated
in cells that were migrating into the fibrin clot and/or remodeling the
ECM. The TG gene has regulatory elements that appear to be responsive
to acute-phase injury cytokines including TGF-ß (26)
,
IL-6 (27)
, and TNF- (28)
. TG's ability to
be induced by TGF-ß (26)
, IL-6 (27)
, and
TNF- (28)
and its association with expression of these
cytokines and VEGF during wound healing indicated a pivotal role during
this process. These cytokines are essential in orchestrating a defined
sequence of events to complete the healing process. TG's association
with these cytokines during wound healing illustrates that the TG gene
could be induced by these cytokines and function to aid in tissue
repair. These findings also indicate that complicated and dynamic
interactions exist between the cytokines and TG.
There is an important interaction between TGF-ß and TG that could
amplify production of granulation tissue. TG is bound to cell surface
complexes comprised of plasminogen, uPAR, and the mannose-6-phosphate
receptor (29)
. The function of this complex is to
facilitate the conversion of latent TGF-ß to its active form
(29)
. Our immunohistochemistry results show maximal
staining for active TGF-ß in areas demonstrating high TG
immunoreactivity when the provisional fibrin matrix is being replaced
by newly synthesized connective tissue. This interaction appears to be
operational in the second phase of wound healing. The increased
activation of TGF-ß by TG could lead to the expression of TG gene
early within the fibrin clot and at sites of re-epithelialization,
since the TG gene itself is induced by TGF-ß. TG and TGF-ß
effectively complete a positive amplification loop whereby the TG
increases TGF-ß activation, which then induces more TGF-ß activity
to further amplify TGF-ß activation and TG expression (Fig. 7)
. The
end product of this process is the replacement of fibrin matrix with
granulation tissue.
The early expression of TG by endothelial cells and macrophages
invading the fibrin clot observed during wound healing appeared to
stabilize the fibrin, since isopeptide bonds were detected in both the
fibrin and the newly synthesized loose granulation tissue. Isopeptide
bonds could be generated by other isoforms of TG, including factor
XIIIa and epidermal transglutaminase. We cannot quantitate to what
extent factor XIIIa or TG is responsible for the generation of
isopeptide bonds. However, the distribution of factor XIIIa in wounds
is different from that of TG antigen reported in this study
(30)
. Earlier studies of patients with factor XIIIa
deficiency have shown wound healing defects in only 20%
(31)
, suggesting an alternate pathway of fibrin
stabilization in the tissues of these patients. Factor XIIIa requires
thrombin for activation while TG is synthesized in an active form
(32)
. The factor XIIIa molecule may be responsible for the
isopeptide bonds formed within the fibrin clot. Since TG does not
require thrombin activation, it can catalyze the stabilization of newly
formed ECM as thrombin is removed from the wounded tissue. The TG in
human blood vessels catalyzes the - cross-links of fibrin and
fibrinogen in human atherosclerotic plaques (33)
,
demonstrating that this enzyme is active during human disease process.
The stabilization of the matrix by TG could regulate assembly of the
granulation tissue and the neovascularization that is essential for an
effective healing response.
The transient expression of TG in the epithelial layer suggested a role
of TG in re-epithelialization and keratinization, as reported by
others. Raghunath et al. (34)
found that TG was expressed
at the dermoepidermal junction in wounds. They suggested that TG might
play a role in attaching the epithelial layer to the dermoepidermal
junction. TG might be responsible for the earlier re-epithelialization
episode, and epidermal transglutaminase takes over later to stabilize
the mature epithelial layer as TG expression diminishes. Deficiency of
epidermal transglutaminase results in ichthyosis, not a total breakdown
of the skin barrier, which suggests there are other transglutaminases
that can maintain epidermal integrity (35)
.
TG could promote wound contraction by cross-linking ECM molecules at
the edge of the wound. Cohen et al. (36)
suggested that
the plasma factor XIII transglutaminases expressed by platelets
contributed to the contraction of the fibrin clot. By ligating protein
molecules throughout the wound, the TG could lead to more effective
wound contraction. The TG expression by skeletal muscle cells and
location of TG activity at these sites could also firmly anchor
granulation tissue with the existing tissues to promote wound closure.
Migration of endothelial and inflammatory cells into fibrin forms an
indispensable part of the healing process. Major proinflammatory and
angiogenic cytokines such as TGF-ß, TNF-, and VEGF exert their
influence by promoting migration of cells to the injured site, and the
scaffolding function of fibrin has been shown to be an essential part
of VEGF-mediated migration of endothelial cells (37)
.
During migration, the stability of the provisional fibrin matrix is of
utmost importance and TG's ability to stabilize the matrix that
resists degradation may be vital for orchestrating tissue repair.
Adding recombinant TG to the sites of skin wound healing caused an
increase in the vessel length density, a measure of neovascularization
in the rat skin. The TG could be an important mediator of angiogenesis
by regulating important events in vascular assembly either directly by
its covalent modification of proteins or indirectly by modifying
TGF-ß function. TGF-ß function is essential for normal vascular
development (38)
, since defects in the TGF-ß binding
protein endoglin lead to the congenital vascular malformation syndrome
of hereditary hemorrhagic telangiectasia (39)
. In ongoing
experiments we have found that TG placed in a fibrin chamber enhances
angiogenesis (unpublished results). Additional studies are in progress
to define the mechanisms responsible for TG-mediated enhancement of
angiogenesis in fibrin.
The proteolytic degradation of the TG may provide a method to regulate the duration and extent of the cross-link reaction. By degrading the TG, the positive amplification loop between TG expression and TGF-ß activation would be disrupted and allow tissue remodeling to occur in the granulation tissue. Extracts from the wound could degrade recombinant TG, which demonstrated that there was proteolytic processing of the TG (unpublished results).
In conclusion, we have established that TG antigen and activity are expressed and function within the wound at sites of neovascularization and granulation tissue formation. TG appears to undergo regulation with the cytokines and directly promote angiogenesis.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Received for publication February 1, 1999. Revised for publication April 8, 1999.
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G. C. Auld, H. Ritchie, L. A. Robbie, and N. A. Booth Thrombin Upregulates Tissue Transglutaminase in Endothelial Cells: A Potential Role for Tissue Transglutaminase in Stability of Atherosclerotic Plaque Arterioscler. Thromb. Vasc. Biol., October 1, 2001; 21(10): 1689 - 1694. [Abstract] [Full Text] [PDF]
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