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Tenascins in fibrotic disorders—from bench to bedside

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Cell Adhesion & Migration
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Although fibrosis is becoming increasingly recognized as a major cause of morbidity and mortality in chronic inflammatory diseases, available treatment strategies are limited. Tenascins constitute a family of matricellular proteins, primarily modulating interactions of cells with other matrix components and growth factors. Data obtained from tenascin C deficient mice show important roles of this molecule in several models of fibrosis. Moreover there is growing evidence that tenascin C has a strong impact on chronic inflammation, myofibroblast differentiation and recruitment. Tenascin C as well as tenascin X has furthermore been shown to affect TGF-β activation and signaling. Taken together these data suggest that these proteins might be important factors in fibrosis development and make them attractive both as biological markers and as targets for therapeutical intervention. So far most clinical research in fibrosis has been focused on tenascin C. This review aims at summarizing our up-to-date knowledge on the involvement of tenascin C in the pathogenesis of fibrotic disorders.
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Tenascins in fibrotic disorders—from bench to bedside
M Kasprzyckaab, C Hammarströmab & G Haraldsenab
a Department of Pathology
b K.G. Jebsen Inflammatory Research Center; University of Oslo and Oslo University
Hospital; Rikshospitalet, Norway
Published online: 20 Mar 2015.
To cite this article: M Kasprzycka, C Hammarström & G Haraldsen (2015) Tenascins in fibrotic disorders—from bench to
bedside, Cell Adhesion & Migration, 9:1-2, 83-89, DOI: 10.4161/19336918.2014.994901
To link to this article: http://dx.doi.org/10.4161/19336918.2014.994901
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Tenascins in brotic disordersfrom bench
to bedside
M Kasprzycka
1,2,
*, C Hammarstr
om
1,2
, and G Haraldsen
1,2
1
Department of Pathology;
2
K.G. Jebsen Inammatory Research Center; University of Oslo and Oslo University Hospital; Rikshospitalet, Norway
Keywords: biomarker, extracellular matrix remodeling, fibrosis, inflammation, tenascin
Abbreviations: MAP—kinases, Mitogen-activated protein kinases; PI3K, Phosphatidylinositol-4, 5-bisphosphate 3-kinase;
PKB, protein kinase B.
Although brosis is becoming increasingly recognized as a
major cause of morbidity and mortality in chronic
inammatory diseases, available treatment strategies are
limited. Tenascins constitute a family of matricellular proteins,
primarily modulating interactions of cells with other matrix
components and growth factors. Data obtained from tenascin
Cdecient mice show important roles of this molecule in
several models of brosis. Moreover there is growing
evidence that tenascin C has a strong impact on chronic
inammation, myobroblast differentiation and recruitment.
Tenascin C as well as tenascin X has furthermore been shown
to affect TGF-bactivation and signaling. Taken together these
data suggest that these proteins might be important factors
in brosis development and make them attractive both as
biological markers and as targets for therapeutical
intervention. So far most clinical research in brosis has been
focused on tenascin C. This review aims at summarizing our
up-to-date knowledge on the involvement of tenascin C in
the pathogenesis of brotic disorders.
Introduction
There is growing recognition in medical and scientific com-
munities that fibrosis, defined as the accumulation of excess
extracellular matrix components, is one of major causes of mor-
bidity and mortality in most chronic inflammatory diseases. In
normal wound healing process, usually reversible, collagen depo-
sition is an essential and beneficial part of wound healing process.
When the wound healing process becomes dysregulated, uncon-
trolled accumulation of matrix components may lead to organ
malfunction and death as seen in end-stage liver disease, kidney
disease, idiopathic pulmonary fibrosis (IPF), and heart failure.
Fibrosis is also observed in many chronic autoimmune diseases,
including scleroderma, rheumatoid arthritis, Crohn’s disease,
ulcerative colitis, myelofibrosis and systemic lupus erythemato-
sus. Despite progress in understanding the mechanisms of
fibrosis, treatment strategies specifically targeting its pathogenesis
are scarce.
1
Tenascins—a family of large oligomeric extracellular matrix
(ECM) glycoproteins consists of 4 members: tenascin C, R, X,
and W
2
sharing similar structure but having different time- and
tissue-specific expression patterns.
3,4
Although present in ECM,
tenascins have rather a signaling than structural role and mostly
affect the interactions of cells with other ECM components and
growth factors in a cell-type- and context- dependent manner.
2
This review focuses on 2 of them, tenascin C and X, as they
had been described in the context of tissue remodeling. Tenascin
C (TNC) is expressed during organ development but its expres-
sion in adult tissue is highly restricted to tissues exposed to high
tensile stress or to high cell turnover. It has been demonstrated
that de novo expression of tenascin C in the adult is usually associ-
ated with injury or cancer.
2-5
In contrast to tenascin C, tenascin
X expression remains high after birth
6
and mutations in this pro-
tein cause Ehlers Danlos syndrome associated with mild
myopathy.
7
Lessons from Animal Models
Growing evidence from animal studies suggests that tenascins,
particularly tenascin C, are crucial to the development of fibrosis
(see Table 1). For example, the contribution of tenascin C to
liver fibrogenesis was demonstrated by El-Karef and colleagues in
the model of immune-mediated hepatitis, induced by intrave-
nous injections of concanavalin A. Collagen deposition and pro-
collagen I and III transcripts levels were significantly lower in
tenasin C deficient (TNKO) mice than in wild type (WT) litter-
mates. Inflammation, measured by the prominence of inflamma-
tory infiltrates and levels of proinflammatory cytokines mRNA
(interferon-g, tumor necrosis factor-a, and interleukin-4), were
higher in WT mice than in TNKO mice, as was the presence of
activated hepatic stellate cells (HSCs) and myofibroblasts. More-
over, transforming growth factor (TGF)-b1 mRNA expression
was significantly upregulated in WT mice, but not in TNKO
mice. It was concluded that tenascin C can promote liver fibro-
genesis through enhancement of the inflammatory response by
cytokine upregulation, HSC recruitment, and TGF-bexpression
during progression of hepatitis to fibrosis.
8
*Correspondence to: Monika Kasprzycka; Email: monika.kasprzycka@rr-
research.no.
Submitted: 09/09/2014; Revised: 11/18/2014; Accepted: 11/24/2014
http://dx.doi.org/10.4161/19336918.2014.994901
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Cell Adhesion & Migration 9:1-2, 83--89; JanuaryApril 2015; © 2015 Taylor & Francis Group, LLC
REVIEW
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In the model of acute lung injury (ALI) induced by intratra-
cheal bleomycin instillation, tenascin C was greatly induced, pri-
marily during the early inflammatory phase. A patchy
distribution of tenascin C protein was found in alveolar septal
walls and secondary septal tips in the areas of damaged tissues.
9
Mice lacking tenascin C are protected from interstitial fibrosis in
this model, because 3 weeks after exposure to bleomycin, TNKO
mice had accumulated 85% less lung collagen than wild-type
mice. The lung interstitium of TNKO mice also appeared to
contain fewer myofibroblasts and fewer cells with intranuclear
Smad-2/3 staining, suggesting impaired TGF-activation or
signaling.
10
Moreover, tenascin C was expressed during the acute stage in
a rat model of myocardial infarction. Additionally, smooth mus-
cle actin (SMA)-positive myofibroblasts appeared in tenascin C
positive areas.
11
Further studies using TNKO mice revealed that
tenascin C controls the dynamics of myofibroblast recruitment
after electrical injury to the myocardium. Although myocardial
repair seemed to proceed normally in TNKO mice, the appear-
ance of myofibroblasts was delayed.
12
Although data obtained from knock-out animals should be
treated with caution due to fact that some effects might be
masked by adaptive response to transgene and even some phe-
notypes might be caused by adaptive mechanisms themselves,
we demonstrate in this review that these observations are consis-
tent with evidence obtained both from in vitro experiments and
clinic.
From Bench: How can Tenascins Inuence Fibrosis?
As presented above, studies in various animal models of fibro-
sis or tissue repair show an important role of tenascin in the out-
come of these disorders. It is therefore valid to ask what is known
about the cellular and molecular mechanisms of tenascins and
their influence on fibrotic processes (see Fig. 1).
Table 1. Selected animal studies examining the role of TNC in models relevant to brotic diseases
Organ Species
Strain /
background Model
Use of knockout
animals Findings
Cornea Mouse C57BL/6 Incision injury Yes Delayed wound healing in TNKO mice with less
myobroblats, reduction in expression of
collagen 1a1, bronectin, TGFb1
63
Heart Rat Lewis Immunization with cardiac C-protein fragments 2
and complete Freunds adjuvant, followed by
intraperitoneal injection of pertussis toxin
No Increase of TNC in experimental autoimmune
myocarditis
64
Heart Mouse BALB/c Infusion of angiotensin II No Increased TNC expression upon myocardial brosis
65
Heart Mouse BALB/c Myocardial injury by an electric pulse Yes Delayed recruitment of myobroblasts in TNKO
mice
12
Heart Mouse BALB/c Ligation of coronary arteries Yes Less brosis in TNKO mice
66
Joints Mouse 129/sv Zymosan-induced inammation Yes Rapid resolution of acute inammation in TNKO
mice
13
Kidney Rat Wistar Diabetic nephropathy induced by high-
carbohydrate-fat food and injection of
streptozotocin
No TNC increased in diabetic nephropathy model.
Deferiprone anti-brotic effect is accompanied
by decrease of TNC expression
67
Lens Mouse C57BL/6 Injury by needle puncture Yes Attenuated EMT in TNKO mice
68
Liver Mouse BALB/c Immune-mediated chronic hepatitis induced by
concanavalin A injections
Yes Attenuated brosis in TNKO mice
8
Liver Rat Wistar Thioacetamide-induced liver cirrhosis Fibrosis after
bile duct ligation
No TNC expressed in most areas of the chronically
injured livers up to 3 and 6 months in bile duct-
ligated and chemically-injured livers,
respectively
69
Lung Mouse C57BL/6 Bleomycin-induced brosis No TNC expression is increased in brotic tissue and
signicantly correlates with de novo
synthesized collagen
70,71
Lung Mouse 129/sv Bleomycin-induced brosis Yes Ameliorated brosis and reduced Smad-3 protein
levels in TNKO mice
10
Lung Rat Sprague-Dawley Bleomycin-induced brosis No Induction of TNC upon brosis
9
Skin Rat Sprague-Dawley Healing skin wounds No TNC expressed during wound healing but not
present in scars
72
Skin Pig Exposure to radiation No TNC expressed in brotic tissue
73
Skin Mouse Swiss Pressure ulcer formation caused by ischemia
reperfusion injury induced by external
application of magnetic plates
No Enhanced TNC and reduced collagen deposition
following propranolol administration
74
Skin Mouse MLR/MpJ Full-thickness excisional skin wound No TNC expressed by blastemal cells
75
Skin Mouse BALB/c Dermatitis induced by application of hapten to the
ear skin
Yes More severe dermatitis in TNKO mice
76
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Tenascins in chronic inflammation
Fibrosis is often a consequence of
chronic/unresolved inflammation. Mid-
wood and coworkers reported that tenas-
cin C acts as an endogenous activator of
TLR4-mediated immunity mediating
persistent synovial inflammation and tis-
sue destruction in arthritic joint disease.
13
In vitro, TLR4 ligation to the fibrinogen-
like (FBG) domain of tenascin C at the
C-terminus of the molecule stimulated
synthesis of TNF-a, IL-6 and IL-8 in pri-
mary human macrophages and IL-6 in
synovial fibroblasts. Interestingly, tenascin
C does not influence the initiation of
joint inflammation but is required for its
maintenance, perhaps reflecting that it is
absent from healthy tissue and needs
induction by inflammatory mediators.
14
In addition to acting as a TLR4 activator,
tenascin C can also stimulate cytokine
synthesis in murine synovial fibroblasts via activation of a9-
integrins.
15
Tenascin C expression in adult tissue is usually associated with
ongoing inflammation for example it is rapidly and transiently
induced in myeloid immune cells in response to tissue injury and
infection. It therefore appears that induction of tenascin C in an
inflammatory setting would drive TLR4 activation leading to
synthesis of more tenascin C, perhaps resulting in a nonresolving
loop of chronic inflammation.
14
Moreover, tenascin C appears to be involved in regulation of
lymphocyte migration as it supports adhesion and rolling of pri-
mary human peripheral blood and tonsillar lymphocytes.
16
Fur-
thermore, tenascin C may be involved in lymphocyte activation,
although both stimulatory and inhibitory effects have been
reported. Tenascin C significantly stimulates the secretion of IL-
5, IL-13, IFN-gand immunoglobulin-E from spleen lympho-
cytes.
17
However, it has an inhibitory effect on the anti-CD3-
induced activation of human peripheral blood T cells.
18,19
Tenascins and myofibroblasts
Myofibroblasts are contractile cells expressing a-smooth mus-
cle actin (a-SMA). They play a crucial role in physiologic wound
healing as well as in profibrotic processes by synthesizing colla-
gens and exerting strong contraction forces to minimize wound
areas (for a comprehensive review of myofibroblast differentia-
tion and functions see ref.
20
) Their recruitment is thought to be
mediated by cellular damage and the release of inflammatory
mediators including TLR agonists.
21
Tamaoki and coworkers
observed that although myocardial repair appeared to proceed
normally in tenascin C-null mice, the appearance of myofibro-
blasts was delayed.
12
Moreover, cardiac fibroblasts from TNKO
mice showed lower cell migration and a-SMA expression than
WT fibroblasts. Both cell migration and a-SMA expression
could be recovered by exposing the fibroblasts to exogenous
tenascin C. Interestingly, the different tenascin C domains were
mapped as responsible for inducing myofibroblast differentiation
and migration: alternatively spliced FNIII repeats and the FBG
domain are responsible for myofibroblast differentiation while
the molecular signal that promoted migration of cardiac fibro-
blasts was mapped to the domain of conserved FNIII repeats and
the FBG domain.
12
Full-length tenascin C was also shown to
promote fibroblast migration within fibrin-fibronectin matrices.
Noteworthy, in opposition to full length molecule, specific frag-
ments of tenascin C have an inhibitory effect on the process.
22
Tenascins and TGF-bactivation and signaling
The differentiation of fibroblasts into collagen-secreting myo-
fibroblasts can be directly induced by transforming growth factor
(TGF-b)
23
—one of the key drivers of fibrosis. TGF-b1 produc-
tion correlates with the progression of liver, lung, kidney, skin
and cardiac fibrosis, and inhibition of its signaling pathway has
been shown to reduce the development of fibrosis in many exper-
imental models.
1
As an example, overexpression of TGF-b1by
renal tubular epithelial cells results in tubulointerstitial fibrosis in
the absence of any injury and, conversely, a blocking antibody to
TGF-bameliorates interstitial matrix accumulation in the fibro-
sis model of unilateral ureteral obstruction (UUO).
24
Likewise,
overexpression of Smad7, an inhibitory factor in the TGF-bsig-
naling pathway, or genetic deletion of the agonistic signaling
molecule Smad3, reduced renal fibrosis in UUO.
25
TGF-bfamily members (TGF-b1, 2, and 3) are synthesized
as pro-proteins that are proteolytically processed before secretion.
Mature TGF-bremains inactive and noncovalently associated
with latency-associated peptide (LAP) in a small latent complex
(SLC). Further binding of LAPs to the latent TGF-b–binding
proteins (LTBPs) form large latent complexes (LLCs) and allows
incorporation of the different latent TGF-bisoforms into extra-
cellular matrices via the LTBPs binding to ECM proteins includ-
ing fibrillins and fibronectin.
26
Activation of the latent TGF-
complex—a crucial step in the regulation of TGF-bfunction can
Figure 1. Cellular and molecular mechanisms by which Tenascin C and X inuence brosis. Tenascin
C participates in maintaining a proinammatory environment and increases migration of broblasts
and myobroblasts. Due to their effects on TGF-bsignaling pathway, tenascin C and X inuence
broblast and epithelial cells differentiation into myobroblasts. Tenascin X modulates mechanical
properties of collagen.
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be mediated by proteolytic cleavage of the LAP and release of
TGF-band/or by a conformational change in the LAP. Activa-
tion of TGF-bmight involve either various cell surface receptors,
such as RGD-dependent integrins, or the ECM protein throm-
bospondin 1.
27
Alcaraz and colleagues have shown that tenascin X activates
the latent TGF-binto an active molecule, most likely through a
conformational change in the latent complex. Authors demon-
strated that fibrinogen-like (FBG) domain of tenascin X physi-
cally interacts with the small latent TGF-bcomplex in vitro and
in vivo and is crucial for the cytokine activation. Moreover,
a11b1 integrin has been identify as a cell surface receptor for
tenascin X.
27
Active TGF-btransduces its signal from cell surface to
nucleus via the canonical Smad-dependent pathway or the non-
canonical pathways including the MAP kinase pathway or PI3K/
Akt/PKB kinase pathway. Upon TGF-bbinding active receptor
I and II complex is formed on the cell surface and phosphorylates
the serine residues at SSXS motif of cytoplasmic Smad2 and
Smad3. The phosphorylated active Smad2/Smad3 heterodimer-
ize with co-Smad Smad4 and translocate to the nucleus where
Smads interact with Smad binding element (SBE) and also
recruit p300 to the transcriptional complex of the target gene.
28
Interestingly, Carey and colleagues observed that the lung
interstitium of TNKO mice treated with bleomycin appeared to
contain fewer myofibroblasts and fewer cells with intranuclear
Smad-2/3 staining, suggesting impaired TGF-bactivation or sig-
naling. In vitro, TGF-bresponse in TNKO lung fibroblasts was
significantly decreased. Impaired TGF-bresponsiveness was cor-
related with dramatically reduced Smad-3 protein levels and
diminished nuclear translocation of Smad-2 and Smad-3 in
TGF-b-exposed TNKO cells. Reduced Smad-3 in TNKO cells
was due to both decreased transcription and enhanced ubiquitin-
proteasome mediated protein degradation.
10
Tenascins and collagen synthesis
A crucial role for tenascin X in collagen biology is suggested
by the fact that its deficiency is associated with Ehlers-Danlos
syndrome in humans.
29
Major clinical symptoms consist of skin
hyperextensibility and joint laxity, while ultrastructural analyses
reveal abnormalities in collagen fibril networks and elastic fiber
morphology. Mice deficient in tenascin X partly reproduced this
phenotype.
30
In vitro studies revealed that tenascin X interacts
with fibrillar collagen type I, III and V when they are in native
conformation.
31
Although the presence of tenascin X does not
significantly influence the main parameters of fibrillogenesis and
diameter of fibrils, mechanical analysis of collagen gels showed
an increased compressive resistance of the gels containing tenas-
cin X, indicating that this protein might be directly involved in
determining the mechanical properties of collagen-rich tissues in
vivo.
32
To Bedside: Tenascin C in Human Fibrotic Disorders
There is growing interest in tenascins in the bio-medical field
including studies on wound healing and fibrotic disorders. So far
the best studied member of the family is tenascin C. Tenascin C
expression is increased in inflammatory and fibrotic diseases in
various organ systems including the lung/pleura, liver, cardiovas-
cular system, intestine and skin (see Table 2).
In human lung and pleural disease, high tissue levels of tenas-
cin C has been reported in diseases such as usual interstitial pneu-
monia (UIP)/idiopathic pulmonary fibrosis (IPF), non-specific
interstitial pneumonia (NSIP), cryptogenic organizing pneumo-
nia (COP), asbestos-induced reactions, postcardiac injury syn-
drome, parapneumonic infection and/or empyema, tuberculosis,
systemic sclerosis-associated pulmonary fibrosis and other rheu-
matoid diseases.
33-37
Tenascin C concentration is furthermore
increased in serum and/or epithelial lining fluid of patients with
usual interstitial pneumonia, sarcoidosis, extrinsic allergic alveoli-
tis, cryptogenic organizing pneumonia and systemic sclerosis-
associated pulmonary fibrosis.
37-40
Increased tissue expression,
especially beneath metaplastic bronchiolar-type epithelium has
been associated with a shortened survival time in patients with
usual interstitial pneumonia.
34
In the gastrointestinal tract, the utility of tenascin C staining
in the diagnosis of minimal collagenous colitis has been sug-
gested.
41
Collagenous colitis is a subgroup of microscopic colitis
that causes watery diarrhea. Biopsy specimens of collagenous coli-
tis, other forms of colitis and normal mucosa were analyzed by
tenascin C immunostaining and compared to conventional histo-
logical and histochemical detection. Selective subepithelial
expression of tenascin-C was found to be highly specific and sen-
sitive for collagenous colitis, especially in minimal collagenous
colitis.
In the liver, the usefulness of tenascin C and 3 other matrix-
derived proteins as serum markers of fibrosis in children with
chronic hepatitis B was investigated.
42
During interferon treat-
ment, tenascin C was significantly decreased in the whole group
and in nonresponders, but there were no significant differences
in mean serum levels of tenascin between children with mild and
advanced liver fibrosis or with mild and severe hepatic inflamma-
tion. Another study
43
showed a significant correlation of serum
levels of tenascin C with the stage of fibrosis in patients with pre-
cirrhotic alcoholic liver disease. However, baseline levels of tenas-
cin C were not significantly correlated to change in histological
stage of fibrosis over 24 months.
There are numerous studies investigating tenascin C in rela-
tion to cardiovascular disease reviewed in refs.
44,45
To mention
some, tenascin C levels are increased in ischemic or dilated car-
diomyopathy
46,47
, calcified heart valves
48
, after myocardial
infarction
49
, in vein grafts
50
, in coronary and carotid athero-
mas
51-52
, in pulmonary arteries with pulmonary arterial hyper-
tension
53
and in aortic aneurysms.
54,55
In patients with chronic renal disease tenascin C was elevated
in serum and urine, and increased with progressive reduction in
renal function, but was unrelated to proteinuria.
56
In skin, transient tenascin C expression is seen during normal
wound healing after excisional wounds and punch biopsies.
57,58
However in keloids, representing a pathological fibrotic response
in skin, increased expression of tenascin C was sustained years
after onset of disease. Tenascin C expression was also higher in
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cultured fibroblasts isolated from keloid lesions compared to
fibroblasts from normal skin.
59
In cornea, tenascin C is induced
in regions of inflammation, fibrosis and neovascularisation but
absent in mature, avascular scar tissue.
60
Expression of tenascin
Cincorneas from patients with bullous keratopathy was higher
than in normal corneas.
61
Bullous keratopathy is a disorder char-
acterized by endothelial dysfunction leading to bullae formation
and subsequent stromal scar formation.
Table 2. Studies examining the expression of TNC in specimens taken from patients with a variety of brotic diseases
Number of
cases/controls Organ Material Cases Controls Findings
51 Lung Biopsy Patients with UIP, DIP, sarcoidosis,
BOOP or allergic alveolitis
Increased TNC in all types,
especially in UIP. In patients with
UIP, increased TNC was
associated with shortened
survival time.
34
15/6 Lung Biopsy Patients with interstitial lung
disease (UIP, NSIP, COP)
Normal lung tissue from cancer
resections
Increase of TNC in UIP, NSIP and
COP.
36
71/5 Lung/pleura Biopsy Patients with pleural inammatory
and brotic diseases
Pleural tissue from patients
undergone surgery for lung
carcinoma
Increase of TNC in areas with
myobroblasts.
35
44/23 Lung Serum Patients with COP, IPF, NSIP Healthy volunteers Serum TNC elevated in patients
with COP.
39
31/15 Lung Serum/ BALF Patients with sarcoidosis Healthy volunteers TNC levels in BALF bur not serum
correlated with pulmonary
inltrates.
40
62/10 Lung Serum Patients with systemic sclerosis Healthy volunteers Increased TNC in sera in SSc patients
with pulmonary brosis.
37
22/6 Lung BALF Patients with UIP, sarcoidosis,
allergic alveolitis
Increase of TNC in patients with
UIP, sarcoidosis and allergic
alveolitis.
38
192/328 Colon Biopsy Collagenous colitis, pronounced
and minimal
Normal mucosa, biopsies from IBD
patients, infectious colitis,
lymphocytic colitis,
pseudomembranous colitis,
ischemic colitis
Increased subepithelial expression of
TNC is highly specicfor
collagenous colitis.
41
47 Liver Serum Children with serologically and
biopsy-veried chronic hepatitis
B
Serum TNC decreased signicantly
during interferon treatment.
42
247 Liver Serum Histologically veried precirrhotic
liver brosis and history of heavy
alcohol consumption
TNC signicantly correlated to the
stage of brosis at baseline but
not with change over time.
43
54/176 Kidney Serum Patients with different types of
glomerulonephritis
Healthy blood bank donors Circulating levels of TNC moderately
higher in patients with chronic
renal disease.
56
4/4 Skin Biopsy Keloid Normal TNC expression was increased in
keloids compared to normal skin
in biopsy specimens and in
keloidal broblasts compared
with normal broblasts in vitro.
59
35/10 Cornea Biopsy Patients undergone penetrating
keratoplasty
Normeal corneas from globes
enucleated for choroidal
melanoma
TNC increased in inammation.
60
40/18 Cornea Biopsy Patients undergone penetrating
keratoplasty
Autopsy corneas TNC increased in corneas affected
by bullous keratopathy.
61
80/15 Systemic
collagen
disease
Serum Patients with various systemic
collagen diseases
Healthy volunteers Serum TNC elevated in patients
with SSc, SSD and LSc.
62
Cardiovascular disease with brotic component Pulmonary arterial hypertension,
stenosis/restenosis, aortic
aneurysm, ischemic or dilated
cardiomyopathy, calcied heart
valves, myocardial infarction.
Increased expression of TNC in
areas with proliferating
myobroblasts reviewed by refs.
44,45
Abbreviations: UIP usual interstitial pneumonia, DIP, desquamative interstitial pneumonia, BOOP bronchiolitis obliterans organizing pneumonia, NSIP non-
specic interstitial pneumonia, COP cryptogenic organizing pneumonia, IPF idiopathic pulmonary brosis, BALF bronchoalveolar lavage uid, IBD inamma-
tory bowel disease, SSc systemic sclerosis, SSD scleroderma spectrum disorder, LSc localized scleroderma
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Lastly, tenascin C is elevated in collagen diseases which are
disorders characterized by inflammation, autoimmune attack and
vascular damage, often leading to fibrosis. Serum levels of tenas-
cin C was elevated in patients with systemic sclerosis, scleroderma
spectrum disorder and localized scleroderma compared to normal
controls.
62
The percentage of diffuse cutaneous systemic sclerosis,
severity of skin thickness and the incidence of pulmonary fibrosis
or pitting scar/ulcers were higher in patients with elevated tenas-
cin C levels than in those without.
In summary, data from human studies has shown increased
levels of tenascin C in tissue, serum and urine in several inflam-
matory and fibrotic diseases. However, studies on the therapeutic
and diagnostic value of tenascin C are few. Perhaps the usefulness
as a serological biomarker is somewhat limited by the fact that
tenascin C more reflect activity of a disease but is unspecific in
terms of etiology. Further studies involving also other members
of family, for example tenascin X, are needed to evaluate possible
potential of tenascins as diagnostic markers and therapeutic tar-
gets in fibrotic diseases.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Funding
This work was funded by grants from the South-Eastern Nor-
way Regional Health Authority to CH and MK.
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... Tenascin-C expression level is decreased in normal tissues, while it is increased in cases of wound healing with remodeling and neo-vascularization, inflammation, and malignancies [6]. Animal experiments suggested that tenascin-C had an important role in the development of fibrosis [6,7]. However, persistent expression of tenascin-C is linked to various pathological conditions, including rheumatoid arthritis (RA), scleroderma, and some fibrotic diseases [8][9][10][11]. ...
... Bubova et al. noted elevated serum tenascin-C levels in individuals with AS relative to healthy controls. While they proposed that tenascin-C levels could indicate chronic structural spinal alterations, they did not find a correlation between tenascin-C levels and disease activity [7]. Gupta et al. examined the levels of tenascin-C in both serum and synovial fluid of individuals with AS and found that serum levels of tenascin-C were elevated in AS patients compared to those in healthy controls. ...
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... TNC encodes for tenascin-C, an ECM glycoprotein that has been shown to engage integrins to elicit cell speci c responses such as brotic responses including collagen synthesis and differentiation of myo broblasts 19 . TNC was upregulated in the TGFβ sample and has been shown to induce myo broblast differentiation and migration 20 . Integrins are the main cell-adhesion transmembrane receptors and bind proteins in the ECM such as bronectin and transduce biochemical and mechanical signals 21 . ...
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... This is the first study to show the expression of these myofibroblast markers in SUI cells although their role in the physiopathology of SUI needs to be addressed. All these genes are expressed in myofibroblasts of several chronic diseases associated with fibrosis and inflammation (Aneiros-Fernandez et al., 2011;Darby et al., 2014;Kasprzycka et al., 2015;Quintanilla et al., 2019;Chen et al., 2021). Here we have shown colocalization of α-SMA and smoothelin in SUI myofibroblast. ...
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Transforming growth factor β (TGF-β) isoforms are secreted as inactive complexes formed through noncovalent interactions between the bioactive TGF-β entity and its N-terminal latency-associated peptide prodomain. Extracellular activation of the latent TGF-β complex is a crucial step in the regulation of TGF-β function for tissue homeostasis. We show that the fibrinogen-like (FBG) domain of the matrix glycoprotein tenascin-X (TNX) interacts physically with the small latent TGF-β complex in vitro and in vivo, thus regulating the bioavailability of mature TGF-β to cells by activating the latent cytokine into an active molecule. Activation by the FBG domain most likely occurs through a conformational change in the latent complex and involves a novel cell adhesion-dependent mechanism. We identify α11β1 integrin as a cell surface receptor for TNX and show that this integrin is crucial to elicit FBG-mediated activation of latent TGF-β and subsequent epithelial-to-mesenchymal transition in mammary epithelial cells.
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Tenascins are extracellular matrix proteins with distinct spatial and temporal expression during development, tissue homeostasis and disease. Based on their expression patterns and knockout phenotypes an important role of tenascins in tissue formation, cell adhesion modulation, regulation of proliferation and differentiation has been demonstrated. All of these features are of importance in stem cell niches where a precise regulation of growth versus differentiation has to be guaranteed. In this review we summarize the expression and possible functions of tenascins in neural, epithelial and osteogenic stem cell niches during normal development and organ turnover, in the hematopoietic and pro-inflammatory niche as well as in the metastatic niche during cancer progression.
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Lung fibrosis is characterized by excessive deposition of extracellular matrix. This not only affects tissue architecture and function, but it also influences fibroblast behavior and thus disease progression. Here we describe the expression of elastin, type V collagen and tenascin C during the development of bleomycin-induced lung fibrosis. We further report in vitro experiments clarifying both the effect of myofibroblast differentiation on this expression and the effect of extracellular elastin on myofibroblast differentiation.
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Background. Tenascin-C (TN-C) is an extracellular matrix glycoprotein that appears at sites of inflammation in cardiac pathologies. Aim of the Work. To evaluate the role of TN-C as a marker for active inflammation in children with dilated cardiomyopathy (DCM). Subjects and Methods. 24 consecutive patients with primary nonfamilial DCM aged 6-72 months (mean 45.19 ± 11.03) were divided into group I, twelve patients with acute onset DCM (<6 months duration), and group II, twelve patients with chronic DCM (>6 months duration), and compared to 20 healthy age- and sex-matched controls. Investigations included estimation of serum TN-C and echocardiographic evaluation using M-mode and 2D speckle tracking echocardiography (STE). Results. Serum TN-C showed a higher significant statistical elevation among patients than controls (P < 0.001) and in group I than group II (P < 0.001). EF was significantly decreased, and LVEDD and EDV increased in patients than controls and in GI than GII. STE showed a statistically significant difference in global peak strain longitudinal (GPSL) average in patients than controls (P < 0.05) and between GI and GII (P < 0.001). STE wall motion scoring showed normokinesia (33.5%), hypokinesia (8.33%), and akinesia (50%) in GI and hypokinesia (100%) in GII. There was a statistically significant positive correlation between serum TN-C and GPSL average. Conclusions. Increased serum TN-C can be used as a marker of inflammation in DCM and is associated with the severity of heart failure and LV dysfunction as detected by STE.
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Fibronectin and tenascin are matrix proteins known to be present in early experimental wound healing. As only limited data are available regarding early matrix changes in human myocardial infarction, the presence of tenascin and fibronectin was studied in human myocardial infarctions of different post-infarction times (6 h to 17 years), using immunohistochemistry. In normal myocardium, fibronectin immunostaining was found in the subendothelial space in vessels. Tenascin was not present in normal myocardium. While fibronectin was demonstrated in the ischaemic cardiomyocytes within 1 day, tenascin was found 4–6 days post-infarction and was located at the margin of the area of infarction. Tenascin expression then shifted from the margin to the centre of the area of infarction, where it could be found 2–3 weeks post-infarction. More than 4 weeks post-infarction, the scar tissue consisted of collagen fibres, with sparse (myo)fibroblasts. By that time, both tenascin and fibronectin expression had disappeared. Another interesting observation in this study was the presence of tenascin, but not fibronectin, surrounding vacuolated glycogen-rich cells, or so-called hibernating cardiomyocytes.
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In adult human skin, the expression of the extracellular matrix glycoprotein tenascin is limited. Under hyperproliferative conditions such as psoriasis and epidermal tumours, dermal tenascin expression is strongly upregulated. The aim of this study was to investigate the pattern and kinetics of tenascin expression in human skin during wound healing and to address the question of whether keratinocytes can directly interact with tenascin during re-epithelialization. Tenascin expression was investigated in excisional wounds in normal human skin, in explants of normal human skin, and in chronic venous ulcers, using immunohistochemistry. No tenascin staining was found directly underneath the leading edge of the sheet of migrating keratinocytes in the excisional wounds and explants. In the excisional wounds and the ulcers, dermal tenascin was strongly upregulated in areas adjacent to hyperproliferative epidermis. These hyperproliferative areas are located approximately 10–50 cells behind the leading edge, as assessed by staining for the Ki-67 antigen and the proliferating cell nuclear antigen (PCNA). At the later stages of normal wound healing and in the chronic ulcers, tenascin was also detected in the wound bed. In these areas, the dermal–epidermal junction stained positive for laminin but was negative for heparan sulphate. The absence of the latter basement membrane component suggests that the formation of a new basement membrane is not completed in these wounds. These findings suggest that tenascin is not a substrate for migrating keratinocytes; that the rapid induction of tenascin expression in the papillary dermis during wound healing results from interaction with the hyperproliferative epidermis; and that in the later stages of wound healing, keratinocytes can potentially interact with tenascin in the wound bed, because the basement membrane of the neo-epidermis is incomplete.
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Aims β-Adrenoceptors modulate acute wound healing; however, few studies have shown the effects of β-adrenoceptor blockade on chronic wounds. Therefore, this study the investigated effect of β1-/β2-adrenoceptor blockade in wound healing of pressure ulcers. Main methods Male mice were daily treated with propranolol (β1-/β2-adrenoceptor antagonist) until euthanasia. One day after beginning of treatment, two cycles of ischemia-reperfusion by external application of two magnetic plates were performed in skin to induce pressure ulcer formation. Key findings Propranolol administration reduced keratinocyte migration, transforming growth factor-β protein expression, re-epithelialization, and necrotic tissue loss. Neutrophil number and neutrophil elastase protein expression were increased in propranolol-treated group when compared with control group. Propranolol administration delayed macrophage mobilization, metalloproteinase-12 protein expression and reduced monocyte chemoattractant protein-1 protein expression. Myofibroblastic differentiation, angiogenesis, and wound closure were delayed in the propranolol-treated animals. Propranolol administration increased neo-epidermis thickness, reduced collagen deposition, and enhanced tenascin-C expression resulting in the formation of an immature and disorganized collagenous scar. Significance β1-/β2-adrenoceptor blockade delays wound healing of ischemia-reperfusion skin injury through the impairment of the re-epithelialization and necrotic tissue loss which compromise wound inflammation, dermal reconstruction, and scar formation.