Achilles Tendinopathy is a Troublesome Sports-related Condition

Involving Blood Vessel Ingrowth into the Tendon Tissue

Studies on the Adjacent Plantaris Tendon and the Peritendinous Connective Tissue

Suggest that TNF-alpha can be Highly Involved in the Vascular and

Tissue Changes

C. Spang

, H. Alfredson

and S. Forsgren

Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, Sweden

Department of Surgical and Perioperative Sciences, Sports Medicine, Umeå University, Umeå, Sweden

Keywords: Achilles Tendinopathy, Peritendinous Tissue, TNF-alpha, TNF Receptor, Blood Vessels, Plantaris Tendon.

Abstract: Achilles tendinopathy/tendinosis is a troublesome condition which is frequently occurring in response to

sports related activities. It can lead to an ending of the sport activity. There is evidence which shows that

ingrowth of blood vessels occurs from the peritendinous tissue. In well-established treatments the areas of

these vessels are targeted. In Achilles tendinosis there is frequently a coalescing of the plantaris tendon with

the Achilles tendon. TNF-alpha is known to be involved in blood vessel remodelling events and

angiogenesis. With these facts as background, the peritendinous connective tissue located inbetween the

plantaris and Achilles tendons and the plantaris tendon itself in cases with Achilles tendinosis were

evaluated concerning expression of TNF-alpha and TNF receptor II (TNFRII). It was found that there were

expressions of TNF-alpha in the numerous cells located in the peritendinous connective tissue and that the

very frequently occurring blood vessels located in this tissue as well as in the tendon tissue exhibited

marked TNFRII reactions. The tenocytes were shown to exhibit moderate TNF-alpha reactions and very

strong TNFRII reactions. The observations suggest that TNF-alpha is highly involved in the blood vessel

remodelling in tendinosis and that TNF-alpha also is involved in tenocyte function.

1 INTRODUCTION

Midportion Achilles tendinopathy, characterized by

chronic Achilles tendon pain, local swelling in the

midportion and loss of function (Khan et al., 1999),

is very frequent among sports athletes. It is assumed

that about 7-9% of professionals performing high

frequency of running and jumping suffer from this

condition (Cook et al., 2002); (Alfredson, 2003).

This makes up 6-18% of all injuries that happen in

running disciplines (Alfredson and Lorentzon,

2000); (Fahlström et al., 2002); (Schepsis et al.,

2002). It has also been shown that even moderate

activity in the form of badminton and track and field

activities can lead to the condition (Kvist, 1991);

(Fahlström et al., 2002). Repetitive strain is

considered to be the main risk factor (Kader et al.,

2002); (Paavola et al., 2002) but other aspects like

age, sex, training performance, muscle weakness and

lack of flexibility seem to be of importance as

background factors (Clement et al., 1984);

(Haglund-Akerlind and Eriksson, 1993); (Tuite et

al., 1997); (Hart et al., 1998); (Dudhia et al., 2007);

(Gaida et al., 2010). The precise underlying

mechanisms are still unclear.

Achilles tendinopathy is often called Achilles

tendinosis when besides pain, swelling and loss of

function, structural tissue changes can be observed

via ultrasound, MRI or histological evaluation (Khan

et al., 1999). A characteristic histological appearance

is the occurrence of an increased vascularization;

other changes are hypercellularity in early states,

decreasing cellularity in later states, cell rounding

and decreased matrix organization (Aström et al.,

1995); (Alfredson et al., 2003); (Riley, 2008). The

blood vessel ingrowth, which occurs from the

peritendinous connective tissue, is presumably of

great importance. It is thus to the regions with high

blood flow, as visualized via colour Doppler coupled

with ultrasonography, that treatments frequently are

Spang C., Alfredson H. and Forsgren S..

Achilles Tendinopathy is a Troublesome Sports-related Condition Involving Blood Vessel Ingrowth into the Tendon Tissue - Studies on the Adjacent

Plantaris Tendon and the Peritendinous Connective Tissue Suggest that TNF-alpha can be Highly Involved in the Vascular and Tissue Changes.

DOI: 10.5220/0004616500450050

In Proceedings of the International Congress on Sports Science Research and Technology Support (icSPORTS-2013), pages 45-50

ISBN: 978-989-8565-79-2

 2013 SCITEPRESS (Science and Technology Publications, Lda.)

directed (Lind et al., 2006); (Alfredson, 2011a).

Currently used treatments for midportion

Achilles tendinopathy/tendinosis such as eccentric

training, injection treatments and traditional surgical

techniques have shown quite good clinical outcome.

However, there are still cases that have not been

found to be curable (Alfredson, 2011a).

Interestingly, it has been shown that 58 out of 73

(80%) Achilles tendinopathy tendons undergoing re-

operation with ultrasound+Doppler guided scraping

have an invaginated or “close by located” enlarged

plantaris tendon (Alfredson, 2011b). During Achilles

tendoscopy, it has also been noted that the plantaris

tendon can be seen to be affixed to the medial side

of the Achilles tendon in cases with tendinopathy

(Van Sterkenburg et al., 2011); (Van Sterkenburg

and Dijk, 2011).

The peritendinous tissue located outside the

Achilles tendon is likely to be of great importance in

the situations with tendinopathy and the curing of

this. It is thus known that this tissue represents a

dynamic and responsive region that markely adapts

to exercise (Kjaer, et al., 2000). It is e.g. shown that

there is an increase in bradykinin and adenosine

concentrations in the peritendinous tissue around the

Achilles tendon in response to exercise (Langberg et

al., 2002). In comparison, it has in recent studies

using a 14C bomb-pulse method been shown that the

tendon tissue itself has a poor regenerative capacity,

i.e. a lack of tissue renewal (Heinemeier et al.,

2013). An important part in the operation procedures

when the plantaris tendon is extirpated is a surgical

scraping procedure, the scraping being done for the

peritendinous connective tissue ventral to the

Achilles tendon (Alfredson, 2011c). The scraping is

guided by the evaluation of where the high blood

occurs, as visualized via ultrasound and laser

Doppler (Alfredson, 2011b).

There is a marked presence of peritendinous

connective tissue in the region between the plantaris

and Achilles tendons. As described above, the two

tendons can be very tightly connected via this tissue

in situations with Achilles tendinosis/tendinopathy.

Almost no attention has been paid to this tissue. The

information that exists says that that there is a

marked presence of blood vessels in the tissue, but

also frequent fibroblasts and to some extent

inflammatory cells as well (Spang et al., 2013).

As described above, the peritendinous connective

tissue outside tendinopathy tendons may be a very

important tissue. It is especially related to the basis

for the ingrowth of blood vessels that occurs from

this into the tendon tissue in tendinosis. Therefore,

this study was undertaken in studies when the

plantaris tendon is extirpated in the situation with

Achilles tendinosis. The signal substance system on

that was focused on was the TNF-alpha system. The

reason is that TNF-alpha is known to be involved in

blood vessel remodelling and angiogenesis (Baluk et

al., 2009); (Ligresti et al., 2011). We have also

previously observed that the tenocytes of the human

Achilles tendon show expression of TNF-alpha as

well as TNF receptors (Gaida et al., 2012).

Antibodies against TNF-alpha and TNF receptor

II (TNFRII) were applied. The hypothesis was that

the TNF-alpha system is involved in the processes in

tendinosis, including in the blood vessel

remodelling.

2 MATERIAL & METHODS

2.1 Individuals

Patients suffering from longterm pain (>3 months) in

the Achilles tendon midportion were included.

Examinations via ultrasound+Doppler showed

thickening, irregular tendon structure but also

hypoechoic regions and high blood flow localized

outside and inside the ventral midportion part

indicating Achilles tendinosis. The evaluated

material consisted of samples from 7 patients: 6 men

with a mean age of 40.2 years and 1 woman with an

age of 58. The samples conformed to specimens of

the plantaris tendon with attached peritendinous

connective tissue. For control purposes a specimen

from an individual without pain symptoms was

evaluated as well (female, 27 years).

2.2 Sampling

During the surgery, the patients were kept under

local anaesthesia (Pilokainhydrochloride 4-5 ml, 10

mg/ml, Astra Zeneca, Södertälje, Sweden). The

procedure was as follows: Via a short longitudinal

skin incision on the medial side the Achilles tendon

was visualized. The plantaris tendon was in these

cases discovered to lie very close to the Achilles

tendon’s medial and ventral part. In some cases it

was even seen to be invaginated. Then the plantaris

tendon was carefully freed distally and proximally

and finally cut at both ends. The tendon tissue was

accompanied by closely attached peritendinous

tissue. The Achilles tendon was thereafter “scraped”

in the regions with high blood flow on the ventral

side according to currently outlined procedures

(Alfredson, 2011c). For control purposes a plantaris

tendon from healthy individual (female, 27 years)

icSPORTS2013-InternationalCongressonSportsScienceResearchandTechnologySupport

was taken as well (c.f. above). Ultrasound+Doppler

showed no pathological features in this case. Due to

ethical reasons the obtaining of control tissue was

restricted in this case.

The study protocol was approved by the

Regional Ethical Board in Umeå (dnr 04-157M;

2011-83-32M). The experiments were conducted

according to the principles expressed in the

Declaration of Helsinki.

2.3 Fixation, Sectioning and Staining

for Morphology

The procedures for fixation and sectioning are in

accordance with previously described procedures for

tendon specimens (Spang et al., 2013); (Gaida et al.,

2012). For demonstration of morphology, sections

were stained with haematoxylin and eosin (H&E).

2.4 Immunofluorescence Processing

Immunostainings for detecting immunoreactions for

TNF-alpha and TNFRII were performed. The

procedures conform to those previously used in our

laboratory for the demonstration of these factors

(Gaida et al., 2012). As secondary antiserum,

fluorescein isothiocyanate (FITC)-conjugated

AffiniPure donkey antigoat IgG (1:100) (code no:

705-095-003, Jackson Immune Research, West

Grove, Pa., USA) was used. Examination was

carried out in a Zeiss Axioscope 2 plus microscope

equipped with epifluorescent technique and an

Olympus DP70 digital camera. The antibodies used

are goat polyclonal antibodies from Santa Cruz

Technology (Santa Cruz, CA, USA). The antibody

for detecting TNF-alpha (L-19, code no.: SC-1350)

was used at a dilution of 1:100 in PBS. The antibody

against TNFRII (C-20, code no.: SC-1074) is

primarily targeted to the C-terminus of human

TNFRII. It was diluted 1:50 in PBS. For further

information on the antibodies, staining procedures

and control stainings, see Gaida et al., (2012).

3 RESULTS

3.1 Morphology

Microscopical analysis of the Htx-Eosin treated

sections showed that the samples contained tendon

tissue and also parts of the peritendinous connective

tissue. There was a large number of fine and large

blood vessels in the peritendinous connective tissue

(Figure 1). There were also very frequent cells in the

tissue. The cells have in a previous study been found

to be stained with antibodies against fibroblast

marker or macrophage marker (Spang et al., 2013).

There was also a large number of blood vessels

within the tendon tissue Compared to the control

specimen the loose connective tissue from tendinosis

patients contained a much higher number of blood

vessels and more cells.

Figure 1: Peritendinous connective tissue between the

plantaris and the Achilles tendon stained for haematoxylin

and eosin. There is a marked presence of blood vessels.

3.2 Immunohistochemistry

3.2.1 TNF-alpha

Immunoreactions for TNF-alpha could be observed

in cells in the peritendinous connective tissue

(Figure 2a) and in tenocytes in the tendon proper

(Figure 2b) in the tendinosis specimens. Weak

reactions could be detected in the walls of blood

vessels located in the tendon proper (Figure 2c) and

in the peritendinous connective tissue (Figure 2d) in

theses specimens. The immunoreactions in the cells

in the peritendinous connective tissue were very

finely point-like. Immunoreactions could also be

observed in the occasionally seen cells in the

peritendinous tissue, to some extent in blood vessel

walls and in tenocytes in the control specimen (not

illustrated).

3.2.3 TNFRII

TNFRII immunoreactions could be detected in the

same type of structures as referred to above in the

tendinosis specimens, namely the cells in the

peritendinous connective tissue, the blood vessel

walls and in tenocytes (Figure 3a-d). The reactions

were strong and seen as small bright dots.

Particularly, the blood vessel reactions were very

marked.

AchillesTendinopathyisaTroublesomeSports-relatedConditionInvolvingBloodVesselIngrowthintotheTendonTissue

-StudiesontheAdjacentPlantarisTendonandthePeritendinousConnectiveTissueSuggestthatTNF-alphacanbeHighly

InvolvedintheVascularandTissueChanges

Figure 2: Immunolabelling for TNF-alpha. Plantaris

tendon with attached peritendinous connective tissue is

shown. Immunoreactions are observed in cells in the

peritendinous connective tissue (a, arrows). Tenocytes in

the tendon proper do also show specific reactions (b,

arrows). Blood vessels in the tendon proper (c) and in the

peritendinous connective tissue (d) are weakly positive for

TNF-alpha (asterisks). Arrows at immunoreactive tenocyte

in (c) and at immunoreactive cells in the peritendinous

connective tissue in (d).

Figure 3: Immunolabelling for TNFRII. Plantaris tendon

with attached peritendinous connective tissue is shown.

Immunoreactions are seen in the cells in the peritendinous

connective tissue (a, arrows) and in tenocytes in the

tendon proper (b,d arrows). Furthermore very marked

immunoreactions are seen in the walls of blood vessels in

both the peritendinous connective tissue (c, asterisks) and

the tendon proper (d, asterisks).

There were thus areas in the peritendinous

connective tissue and in tendon tissue proper that

exhibited widespread TNFRII reactions (Fig.3c,d).

Immunoreactions were also noted for the blood

vessel walls and to some extent for the tenocytes and

the cells in the peritendinous connective tissue in the

control specimen.

4 DISCUSSION

These evaluations show for the first time the

occurence of TNF-alpha and TNFRII immuno-

reactions in the plantaris tendon and in the

peritendinous connective tissue between the

plantaris tendon and the Achilles tendon in cases

with Achilles tendinosis. It is evident that there is a

local TNF-alpha production in cells in this tissue and

that TNF-alpha is involved in the blood flow

regulation of the tissue. There were thus very

marked TNFRII reactions in the vessel walls. To

some extent there were similar reaction patterns in

the control specimen. However, it should be

underscored that the vessels and the cells in the

peritendinous connective tissue were much fewer

than what was case for the tendinosis specimens.

Due to ethical reasons, the obtaining of control

samples was restricted to one individual.

Concerning the marked TNFRII immuno-

reactions seen for blood vessel walls it is noteworthy

that this TNF receptor is shown to enhance

angiogenesis under low oxygen conditions (Luo et

al., 2006). TNF-alpha is on the whole known to be

involved in blood vessel regulation. It is e.g. shown

that TNF-alpha is involved as an early component in

the cascade leading to angiogenesis in response to

aortic injury (Ligresi et al., 2011). The origin of the

TNF-alpha in this case was macrophages (Ligresi et

al., 2011). Renal ischemia is shown to be

accompanied by increased expressions of TNF-alpha

and TNF receptors, an increased expression of

TNFRII being observable for the renal arteries and

the neuroretina (Gesslein et al., 2010).

TNFRII, as well as TNF-alpha, immuno-

reactions were also observed for tenocytes of the

plantaris tendons. The situation is thus the same as

was previously observed for the human Achilles

tendon (Gaida et al., 2012). This can imply that

autocrine/paracrine TNF-alpha effects occur for the

tenocytes, effects which can be related to trophic

functions. In accordance with this suggestion, it is

known that binding at TNFRII is related to tissue

repair, growth-modulating effects and differentiation

(Ihnatko and Kubes, 2007). Due to the “compression

icSPORTS2013-InternationalCongressonSportsScienceResearchandTechnologySupport

theory” the compressive forces on the peritendinous

tissue can be very strong in Achilles tendinosis

(Cook and Purdam, 2009). Therefore, tissue repair,

growth-modulating influences and differentiation

might play key roles during the tendinosis condition.

TNF-alpha blockers have been tested for patients

suffering from chronic Achilles tendinopathy

(Fredberg and Ostgaard, 2009). The clinical

implication however is still unclear. The results of

the present study indicate that further studies should

be undertaken concerning the use of anti-TNF

treatments.

In conclusion it is here shown that there is a

marked presence of the TNF-alpha system in the

situation with plantaris tendon involvement in

Achilles tendinosis. TNF-alpha is produced in the

peritendinous connective tissue and may be highly

involved in the blood vessel remodelling as well as

for tenocyte function. These findings stress that the

TNF-alpha system might be an important system in

a condition that is frequently involved for sports

active persons, namely Achilles tendinopathy/

tendinosis.

ACKNOWLEDGEMENTS

The authors acknowledge Ms Ulla Hedlund for

excellent technical services. Financial support was

obtained from the Faculty of Medicine at Umeå

University and the Swedish National Centre for

Research in Sports.

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