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Inflammation Is Present in Early Human Tendinopathy

Neal L. Millar, Axel J. Hueber, James H. Reilly, Yinghua Xu, Umberto G. Fazzi, George A. C. Murrell and Iain B.
McInnes
Am J Sports Med 2010 38: 2085 originally published online July 1, 2010
DOI: 10.1177/0363546510372613

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Inflammation Is Present in Early
Human Tendinopathy
Neal L. Millar,*y MBChB, MRCS, Axel J. Hueber,y MD, James H. Reilly,y Yinghua Xu,z MBBS,
Umberto G. Fazzi,§ FRCS (Ortho), George A. C. Murrell,z MBBS, DPhil (Oxon), MD, and
Iain B. McInnes,y PhD, FRCP, FRSE
From the yDivision of Immunology, Infection and Inflammation, University of Glasgow, Glasgow,
Scotland, United Kingdom, zOrthopaedic Research Institute, Department of Orthopaedic
Surgery, St George Hospital Campus, University of New South Wales, Sydney, Australia, and
§
Department of Orthopaedic Surgery, Western Infirmary, Glasgow, Scotland, United Kingdom

Background: The cellular mechanisms of tendinopathy remain unclear particularly with respect to the role of inflammation in early
disease. The authors previously identified increased levels of inflammatory cytokines in an early human model of tendinopathy
and sought to extend these studies to the cellular analysis of tissue.
Purpose: To characterize inflammatory cell subtypes in early human tendinopathy, the authors explored the phenotype and quan-
tification of inflammatory cells in torn and control tendon samples.
Design: Controlled laboratory study.
Methods: Torn supraspinatus tendon and matched intact subscapularis tendon samples were collected from 20 patients under-
going arthroscopic shoulder surgery. Control samples of subscapularis tendon were collected from 10 patients undergoing
arthroscopic stabilization surgery. Tendon biopsy samples were evaluated immunohistochemically by quantifying the presence
of macrophages (CD68 and CD206), T cells (CD3), mast cells (mast cell tryptase), and vascular endothelium (CD34).
Results: Subscapularis tendon samples obtained from patients with a torn supraspinatus tendon exhibited significantly greater
macrophage, mast cell, and T-cell expression compared with either torn supraspinatus samples or control subscapularis-
derived tissue (P \ .01). Inflammatory cell infiltrate correlated inversely (r 5 .5; P \ .01) with rotator cuff tear size, with larger
tears correlating with a marked reduction in all cell lineages. There was a modest but significant correlation between mast cells
and CD34 expression (r 5 .4; P \ .01) in matched subscapularis tendons from shoulders with supraspinatus ruptures.
Conclusion: This study provides evidence for an inflammatory cell infiltrate in early mild/moderate human tendinopathy. In par-
ticular, the authors demonstrate significant infiltration of mast cells and macrophages, suggesting a role for innate immune path-
ways in the events that mediate early tendinopathy.
Clinical Relevance: Further mechanistic studies to evaluate the net contribution and hence therapeutic utility of these
cellular lineages and their downstream processes may reveal novel therapeutic approaches to the management of early
tendinopathy.
Keywords: tendinopathy; inflammation; supraspinatus; shoulder

*Address correspondence to Neal L. Millar, MBChB, MRCS, Arthritis

Research UK/RCSEd Orthopaedic Clinical Research Fellow, Specialist
Registrar in Orthopaedics, Division of Immunology, Infection and Inflam-
mation, Glasgow Biomedical Research Centre, University of Glasgow,
120 University Avenue, Glasgow G12 8TA Scotland, United Kingdom
(e-mail: n.millar@clinmed.gla.ac.uk).
One or more authors has declared a potential conflict of interest: This
work was funded by grants from the Arthritis Research UK Orthopaedic
Clinical Research Fellowship, the Royal College of Surgeons of Edinburgh
Cutner Fellowship, and the German Research Foundation Fellowship (DFG).
The American Journal of Sports Medicine, Vol. 38, No. 10
DOI: 10.1177/0363546510372613
Ó 2010 The Author(s)
Overuse tendon injuries, namely tendinopathies, pose
a significant problem in sports and exercise medicine.17
The intrinsic pathogenetic mechanisms underlying the
development of tendinopathies are largely unknown and
debate continues as to whether inflammatory processes
play a prominent role in the disease process.1 Empirically,
by dint of the ‘‘danger hypothesis’’26 innate immune
mechanisms should at first support core effector biology
upon early damage mediated by biomechanical stress.
Historically, ‘‘tendonitis’’ was used to describe chronic
pain from a symptomatic tendon,7 implying that inflam-
mation was a central pathologic process. However,

2085
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2086 Millar et al
traditional treatment modalities aimed at modulating
inflammation have enjoyed limited success.2,5 Histologic
studies that focused on symptomatic (late) biopsy compo-
nents reveal few or absent inflammatory cells but rather
implicated substantial degenerative changes comprising
hypoxia, hyaline, mucoid, or myxoid degenerations in
over 85% of biopsy specimens.16,22
In contrast to the foregoing, recent studies implicate an
early, important inflammatory component in disease pro-
cesses. Molloy et al31 performed microarray studies on
a running rat supraspinatus tendinopathy model and
showed upregulation of key inflammatory cell receptors
and immunoglobulins. Barbe et al,4 using a cumulative
trauma disorder rodent model, showed increased infiltrat-
ing macrophages compared with controls. Human tissue
biopsy samples from small rotator cuff tears taken at the
time of surgery show a significant inflammatory infiltrate,
consisting of macrophages and mast cells, compared with
larger tears, reflecting a more degenerative picture.25
One of the major limitations of human studies is that
tendon biopsy specimens are usually obtained when
patients are symptomatic and therefore biopsy material
is likely to represent chronic, rather than early phase, ten-
dinopathy. We previously suggested that matched subscap-
ularis tendon from patients with full-thickness rotator cuff
tears may be a model of early human tendinopathy based
on histologic appearances and significantly increased levels
of cytokines and apoptotic markers in these tissues.29 The
purpose of this study was to formally characterize inflam-
matory cell subtypes within this putative model.
METHODS
Human Model of Tendinopathy
All procedures and protocols were approved by the Ethics
Committee under ACEC No. 99/101. Twenty supraspina-
tus tendon samples were collected from patients with
rotator cuff tears undergoing shoulder surgery during
2008 and 2009 (Table 1). The mean age of the rotator
cuff–ruptured patients was 57 years (range, 39-75 years)
and the mean tear size was 2.8 cm2. Samples of the sub-
scapularis tendon were also collected from the same
patients. Patients were only included if there was no clin-
ically detectable evidence of subscapularis tendinopathy
on a preoperative MRI scan or macroscopic damage to
the subscapularis tendon at the time of arthroscopy; by
these criteria, they represented a truly preclinical cohort.
An independent control group was obtained, comprising
10 samples of subscapularis tendon collected from
patients undergoing arthroscopic surgery for shoulder
stabilization without rotator cuff tears in the same time
period. The absence of rotator cuff tears was confirmed
by arthroscopic examination. The mean age of the control
group was 35 years (range, 20-41 years).
Tissue Collection and Preparation
Arthroscopic repair of the rotator cuff was carried out
using the standard 3-portal technique as described by
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The American Journal of Sports Medicine
Wu et al.40 The cross-sectional size of the rotator cuff
tear was estimated and recorded as described previously.9
The subscapularis tendon was biopsied arthroscopically
from the superior border of the tendon 1 cm lateral to the
glenoid labrum. The supraspinatus tendon was biopsied
from within 1.5 cm of the edge of the tear before surgical
repair. For immunohistochemical staining the tissue sam-
ples were immediately fixed in 10% (v/v) formalin for 4 to 6
hours and then embedded in paraffin. Sections were cut to
5-mm thickness using a Leica-LM microtome (Leica Micro-
systems, Wetzlar, Germany) and placed onto Superfrost
Ultra Plus glass slides (Gerhard Menzel, Braunschweig,
Germany). The paraffin was removed from the tissue sec-
tions with xylene, rehydrated in graded alcohol, and used
for histologic and immunohistochemical staining per previ-
ously established methodologies.28
Histology and Immunohistochemistry Techniques
Sections were stained with hematoxylin and eosin and
toluidine blue for determination of the degree of tendino-
pathy as assessed by a modified version of the Bonar score19
(4 5 marked tendinopathy, 3 5 advanced tendinopathy, 2 5
moderate degeneration, 1 5 mild degeneration, 0 5 normal
tendon). This included the presence or absence of edema
and degeneration together with the degree of fibroblast cel-
lularity and chondroid metaplasia. Thereafter, sections
were stained with primary monoclonal antibodies directed
against the following markers: CD68 (pan macrophages),
CD3 (T cells), CD4 (T helper cells), CD34 (endothelial
marker), CD206 (M2 macrophages), and mast cell tryptase
(mast cells). Endogenous peroxidase activity was quenched
with 3% (v/v) H2O2, and nonspecific antibody binding
blocked with 2.5% horse serum in TBST (tris-buffered saline
with Tween) buffer for 30 minutes. Antigen retrieval was
performed in 0.01-M citrate buffer for 8 minutes in a micro-
wave. Sections were incubated with primary antibody in
2.5% (w/v) horse serum/human serum/TBST at 4°C over-
night. After 2 washes, slides were incubated with Vector
ImmPRESS Reagent kit (Vector Laboratories, Burlingame,
California) as per manufacturer’s instructions for 30
minutes. The slides were washed and incubated with Vector
ImmPACT DAB chromagen solution, followed by extensive
washing. Finally, the sections were counterstained with
hematoxylin. Positive (human tonsil tissue) and negative
control specimens were included, in addition to the surgical
specimens for each individual antibody staining technique.
Omission of primary antibody and use of negative control
isotypes confirmed the specificity of staining.
We applied a novel scoring system based on previous
methods6 to quantify the immunohistochemical staining.
Ten random high-power fields (3400) were evaluated by
3 independent blinded assessors (A.J.H., J.H.R., and Y.X.).
In each field, the number of positive and negatively stained
cells were counted, the percentage of positive cells calcu-
lated, and the mean percentage of the 3 reviewers’ ratings
calculated, giving the following semiquantitative grading:
grade 0 5 no staining, grade 1 5 \10% cells stained posi-
tive, grade 2 5 10% to 20% cells stained positive, and grade
3 5 .20% cells positive. In addition, the blood vessel
Vol. 38, No. 10, 2010
TABLE 1
Patient Demographics and Rotator Cuff Tear Size
Tear Size Control
Number of cases 10
Mean age in years (range) 35 (20-41)
Mean duration of symptoms in months (range) 8.3 (1-14)
Mean number of steroid injections 0 1.2
Figure 1. Relative expression of cell markers in human
tendon samples. Histologic scoring system: 0 5 no stain-
ing, 1 5 \10% cells positive, 2 5 10% to 20% cells posi-
tive, grade 3 5 .20% cells positive. Data displayed as
mean 6 standard error of the mean; n 520 for supraspina-
tus and matched subscapularis, n 510 for control group.
*P \ .01; **P \ .001.
numbers were assessed in the same random high-power
fields. Intrarater reliability was good, reflected in r 5 .82.
Statistical Analysis
Results are reported as mean values 6 standard error of
the mean (SEM). Comparisons between groups were
made with 2-way paired Student t tests, Mann-Whitney
U tests, and Kruskal-Wallis 1-way analysis of variance
on ranks, using Sigma Stat, version 3.1 (Systat Software
Inc, Richmond, California). A power analysis was per-
formed with the beta error set at 0.2 (power 5 0.8). Based
on the results of the power analysis, it was determined that
each group required 10 tissue samples to detect a difference
of 20% between each of the groups with regard to inflam-
matory cell subset expression.
RESULTS
Histologic Changes
All torn supraspinatus samples showed grade 4 changes
consistent with marked degeneration, mucoid change,
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Inflammation in Early Tendinopathy 2087
Small (\1 cm2) Medium(.1-3 cm2) Large (.3-5 cm2) Massive (.5 cm2)
6 7 4 3
51 (39-60) 57 (48-64) 55 (47-60) 63 (50-75)
7.8 (2-18) 7.0 (3-13) 8.8 (4-22) 6.3 (2-15)
1.6 1.5 1.8
and frank chondroid metaplasia. The massive tears had
reduced fibroblast cellularity and greater chondroid meta-
plasia compared with all other tears (P \ .05). Despite
their normal MRI and arthroscopic appearances, matched
subscapularis tendon showed grade 2 to 3 changes indica-
tive of moderate/advanced tendinopathy. All control sam-
ples were classified as grade 1, consistent with normal
fibrotendinous tissue with large distinct collagen fibrils.
There were no significant correlations between Bonar
score19 and the mean duration of symptoms or age of the
patient cohort. This is similar to a cohort of patients
reported previously.29
Inflammatory Cell Changes
The cohort of subscapularis tendon samples exhibited sig-
nificantly greater (P \ .01) staining for macrophages,
mast cells, and T cells compared with both matched torn
supraspinatus samples and control tissue (Figure 1). Mac-
rophages were scattered mainly throughout the subintimal
layers, although some were present in a perivascular cuff.
The majority of mast cells were located around the vascu-
lature, with the remainder residing in the synovial lining
or scattered throughout the tissue. Inflammatory cell infil-
trate correlated inversely (r 5 .5; P \ .01) to rotator cuff
tear size in the torn supraspinatus tendon samples, with
larger tears showing a marked reduction in all cell types.
In particular, mast cells and M2 macrophages were seen
in specimens with increased fibroblast cellularity and
decreased markedly in number as the fibroblast cellularity
of the specimen decreased (Figure 2). There was a moderate
but significant correlation between mast cells and CD34
expression (r 5 .4; P \ .01). No significant associations
were noted between inflammatory infiltrate and the age
of patients or duration of symptoms.
Vascular Changes
The CD34 positive vessels were found in the greatest quan-
tity in matched subscapularis samples compared with all
other groups, with a mean vessel count of 38 6 2 in subsca-
pularis compared with 15 6 3 in matched torn biopsy sam-
ples or 6 6 1 in control tissues. As tear size increased in the
supraspinatus samples, there was a significant (P \ .05)
reduction in vascularity, suggesting an inverse relation-
ship. The mean vessel count was significantly (P \ .01) dif-
ferent between all tear groups (Table 2).
2088 Millar et al The American Journal of Sports Medicine

Figure 2. Immune staining for mast cells and macrophages. Central overview picture shows mast cell tryptase positive staining in
matched subscapularis tendon at cut edge. Asterisk (*) indicates vessels (magnification 3100); black line represents 200 mm.
Mast cell tryptase in normal unmatched supraspinatus tendon (A), torn human supraspinatus tendon (B), and matched subsca-
pularis tendon (C); and CD 68 macrophages in normal unmatched supraspinatus tendon (D), torn human supraspinatus tendon
(E), and matched subscapularis tendon (F). Isotype controls are shown in small photographs in bottom left of image (magnification
3400). Black line represents 50 mm.

Inflammaon

Mechanical Stress

Tenocytes
Macrophages Mast cells

Cytokines
O2 free radicals Angiogenic factors
Proteases Growth factors
Cytokines

Proinflammatory Neoangiogenesis
Degeneraon Reparave process

Early Tendinopathy

Figure 3. Schematic diagram illustrating the manner in which early tendinopathy may arise because of inflammation. An increase
in the amount and duration of load that a tendon cell experiences results in the release of various inflammatory, angiogenic, and
growth factors that interact to drive the tendon matrix toward a degenerative or reparative process.
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Vol. 38, No. 10, 2010 Inflammation in Early Tendinopathy 2089

TABLE 2
Histologic Features in Control, Matched Subscapularis, and Torn Supraspinatus Tendon Samples

Torn Supraspinatus
Control Matched Overall Small Medium Large Massive
Feature (n 5 10) Subscapularis (n 5 20) (n 5 20) (n 5 6) (n 5 6) (n 5 4) (n 5 4)

Mean vessel counta 661 38 6 2 15 6 3 28 6 2 17 6 2 6 61 161

Inflammatory cell countb
Macrophages 4 6 1 30 6 4 13 6 2 23 6 1 14 6 2 5 6 1 3 6 1
Mast cells 0 6 0.5 25 6 3 10 6 3 18 6 4 11 6 1 4 6 1 4 6 2
M2 macrophages 2 6 1 26 6 3 9 6 2 15 6 2 13 6 2 7 6 2 2 6 1
T cells 1 6 1 12 6 2 6 6 2 9 6 2 7 6 1 3 6 1 2 6 1

a
Mean number of vessels in 10 high-power fields of view (magnification 3400).
b
Mean number of cells in 10 high-power fields of view (magnification 3400).

DISCUSSION play a critical role in the initiation, maintenance, and res-

This study is the first to provide convincing evidence of an
inflammatory cell infiltrate in early mild/moderate human
supraspinatus tendinopathy. Our data therefore directly
inform the controversy that surrounds the role for inflam-
mation in the development of tendinopathies.
Experimental models provide good evidence of an early
inflammatory response. A running rodent model of tendin-
opathy is associated with upregulation of key inflammatory
modulators,31 including the 5-lipoxygenase activating
protein (FLAP) and cyclooxygenase at early and inter-
mediate time points.33 In rabbit and equine models, exces-
sive mechanical load induces acute inflammatory cell
infiltrates.3,24 Human studies are less convincing.
Whereas some studies describe the presence of increased
cytokine expression11,29,38,41 as proof of an inflammatory
component, virtually all histologic studies in human tis-
sue have failed to demonstrate inflammatory cells in ten-
dinopathic samples.16,18,19,22,39 One of the previous
limitations has been that such tissues were from patients
with advanced disease, presumably dominated pathologi-
cally by chronic degenerative changes. Recent human
biopsy work in tendons with smaller tears25 with a less
degenerative picture revealed a significant inflammatory
infiltrate of mast cells and macrophages. Inflammation is
also intimately linked to the Fas/Fas ligand system of apo-
ptosis, which has been found in excessive amounts in
a range of tendinopathies.20,32,42 Our data provide con-
vincing evidence that inflammation is indeed present
and could therefore provide a molecular link to key path-
ologic events in tendinopathy.
Our previous work on matched subscapularis tendon
biopsy specimens from patients with a full-thickness
supraspinatus tear produced unexpected results.30 We
found that despite normal MRI or arthroscopic appearan-
ces, at the histologic level, the tendon had mild/moderate
tendinopathic changes. These samples contained increased
expression of proinflammatory cytokines compared with
controls assessed at the mRNA level.29 We have now
extended these observations to include a detailed cellular
analysis of a new cohort of similar patients. Macrophages
olution of inflammation.12 In response to cytokines and
microbial products, mononuclear phagocytes develop spe-
cialized and polarized functional properties within func-
tionally discrete M1 or M2 subsets.23 M1 macrophages
are efficient producers of effector moieties, including reac-
tive oxygen and nitrogen intermediates and inflammatory
cytokines and chemokines, whereas in general, M2 macro-
phages act to dampen inflammatory responses and scavenge
debris as well as promote angiogenesis. M2 macrophages
express fibronectin and insulin growth factor–1, key signals
for tissue repair,34 and recent work has shown that defec-
tive M2 polarization resulted in impaired muscle tissue
repair mechanisms.35 We detected a significant proportion
of macrophages expressing CD206, compatible with an M2
phenotype. Inflammation in early tendinopathy could in
part reflect an attempt at tissue repair. The associated
higher blood vessel density in back-to-back sections of ten-
don samples is compatible with this hypothesis.
Of particular interest is the large number of mast cells
present in early tendinopathy. Mast cells play a key role
in the inflammatory process; they rapidly release charac-
teristic granules and various mediators that mediate the
recruitment and activation of monocytes, neutrophils,
dendritic cells, B cells, and T cells14,37 and have recently
been linked to neoangiogenesis.8 They are associated
with inflammatory diseases including atopic dermatitis,10
scleroderma,13 and rheumatoid arthritis.27 Scott et al36
found significantly increased mast cell numbers in human
patellar tendinosis and correlated this with symptom
duration and vascular hyperplasia, while studies in rab-
bits have shown that mast cells and their mediators influ-
ence fibroblast activity and vascular permeability.15 In
keeping with these previous studies, our findings are
strongly suggestive of a key proangiogenic role for mast
cells in tendinopathies. Indeed, mast cells may play
a role in ‘‘stress-induced’’ tendinopathy by degranulating
in response to mechanical stress, thereby releasing mast
cell tryptase and other vasoactive and angiogenic media-
tors that are important in the balance between repair
and further degeneration (Figure 3). This observation
warrants further mechanistic studies to understand how

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2090 Millar et al
mast cells interact with tenocytes and regulate matrix
synthesis.
There are limitations inherent in our study. First, as
the control group was substantially younger than the
patient group, age-related changes within the tendon
samples could contribute to the degenerative picture
and inflammatory cell expression seen in the matched
subscapularis tendons. However the lack of degenerative
change on MRI and arthroscopic examinations suggests
that the differences are truly at the cellular level as sug-
gested by our work. Second, the subscapularis tendon is
functionally and organizationally distinct from supraspi-
natus and thus responds to mechanical loading in a differ-
ent manner that may alter its cellular profile. Also,
control samples from subscapularis undergoing stabiliza-
tion may not be truly ‘‘normal’’ controls but are currently
the best available control tendon samples, and this is
reflected by a Bonar score of 0. It is reassuring, however,
that we found the same inflammatory and vascular cell
subtypes in matched subscapularis tissue, indicating
that the inflammatory response may be uniform within
joints subjected to tendon degeneration. In addition, hav-
ing subscapularis samples from the same patient elimi-
nates bias that may result from variation between
individuals and has been previously shown to be a useful
method in sampling of tissues.21
CONCLUSION
In summary, we have found a distinct inflammatory infil-
trate in early human tendinopathy. Better understanding
of this inflammatory cascade should lead to the develop-
ment of cell-targeted treatment modalities for early supra-
spinatus tendinopathy.
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