t h e s u r g e o n x x x ( 2 0 1 7 ) 1 e6

Available online at www.sciencedirect.com

ScienceDirect
The Surgeon, Journal of the Royal Colleges
of Surgeons of Edinburgh and Ireland
www.thesurgeon.net

Inflammation in tendinopathy

Alessio D'Addona a,*, Nicola Maffulli b,c, Silvestro Formisano d,

Donato Rosa a
a
Department of Public Health, Section of Orthopaedic and Trauma Surgery, School of Medicine and Surgery,
University of Naples “Federico II”, Via Pansini 5, 80131, Naples, Italy
b
Centre for Sports and Exercise Medicine, Barts and The London School of Medicine and Dentistry, Mile End Hospital,
275 Bancroft Road, London, E1 4DG, England, UK
c
Department of Musculoskeletal Disorders, Faculty of Medicine and Surgery, University of Salerno, Salerno, Italy
d
Department of Molecular Medicine and Medical Biotechnology, School of Medicine, Federico II University of Naples,
Via Pansini 5, 80131, Naples, Italy

article info abstract

Article history: Pain and functional limitation are frequent in symptomatic tendinopathy. The essential
Received 4 April 2016 lesion of tendinopathy is a failed healing response. Understanding the cellular and mo-
Received in revised form lecular mechanisms involved in a failed healing response during the early stages of
7 April 2017 pathogenesis of tendinopathy would help to develop new and effective treatments. The
Accepted 25 April 2017 role of inflammation in the development of tendon pathologies has been revived during the
Available online xxx last few years, in particular during the first phases of tendinopathies, when “early ten-
dinopathy” may not be clinically evident. This review outlines the possible molecular
Keywords: events that occur in the first phases of tendinopathy onset, stressing the role of pro-
Inflammation inflammatory cytokines, proteolytic enzymes, growth factors and healing genes in the
Early tendinopathy development of tendon disorders.
Healing © 2017 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and
Pro-inflammatory cytokines Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.

many causes have been hypothesised.4 Hypoxia, ischaemic

Introduction
Tendinopathy is the best generic descriptive term for the
clinical conditions in and around tendons arising from over-
use.1,2 The term “tendinopathy” defines the clinical syndrome
characterised by a combination of pain, swelling and impaired
performance.3 Tendon injuries produce considerable
morbidity, and the disability that they cause may last for
several months despite what is considered appropriate man-
agement. The aetiology of tendinopathy remains unclear, and
damage, oxidative stress, hyperthermia, impaired apoptosis,
inflammatory mediators, fluoroquinolones, and matrix met-
alloproteinase imbalance have all been implicated as mech-
anism of tendinopathies.4 Biomechanical factors, functional
alterations, repetitive mechanical loading, aging and meta-
bolic disorders may predispose to tendinopathy, with high
risk of re-injury.1,2,5
The process of tendinopathy involves both the collagen
matrix and the tenocytes.6 Normally, collagen fibers in ten-
dons are tightly bundled in a parallel fashion, but

* Corresponding author. Fax: þ39 081 7463722.

E-mail addresses: alessio.daddona@gmail.com (A. D'Addona), n.maffulli@qmul.ac.uk (N. Maffulli), sformisano@unisa.it
(S. Formisano), drosa@tin.it (D. Rosa).
http://dx.doi.org/10.1016/j.surge.2017.04.004
1479-666X/© 2017 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland.
Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: D'Addona A, et al., Inflammation in tendinopathy, The Surgeon (2017), http://dx.doi.org/10.1016/
j.surge.2017.04.004
2 t h e s u r g e o n x x x ( 2 0 1 7 ) 1 e6
tendinopathic samples show unequal and irregular crimping,
loosening and increased waviness of collagen fibers, with an
increase in type III reparative Collagen (COL-III).6e8
Overloading of tendons after intensive exercises and
training induces micro-rupture of tendon,9 with the expres-
sion of damage associated molecular patterns (DAMPs) in an
attempt to produce tissue healing.10 The essential lesion of
tendinopathy is not of a degenerative nature: it has the fea-
tures of a failed healing response, in which the tendon at-
tempts to heal, but, for some reason, including, possibly,
continuous inappropriate mechanical stimuli, the healing
process appears non-finalised.3 Several models have recently
implicated pro-inflammatory cytokines to initiate the cata-
bolic process, such as Tumor Necrosis Factor-a (TNF-a),
Interleukin-1 b (IL-1b) and Interleukin-6 (IL-6), Growth Factors
such as Fibroblast Growth Factor (FGF), Vascular Endothelial
Growth Factor (VEGF), TGF-b, EGF, IGF-1,1 and transcriptional
factors such as Nuclear Factor-kappa B (NF-kB), especially in
the earlier phases of the process.11
In the acute phase, it is possible to find signs of in-
flammations with a huge release of cytokines and immuno-
modulating factors able to cause inflammation with cellular
proliferation, onset of pain and ECM degradation with
necrosis.12,4,12e15 This phase could be considered a prelude to
the clinical condition, in which there is an initial production
and release of cytokines and attempts at healing.16 When the
amount of inflammatory cells, derived from overloading and
mechanical stress, becomes relevant, there is an imbalance
between pro-inflammatory factors with degradation of ECM,
and protective factors, causing onset of pain, by the release of
Substance P and glutamate and the production of COX2 and
PGE2.3,16,17
The homeostasis of tendons results from a continuing
remodeling process mediated by MMPs (matrix metal-
loproteases) and TIMPs (inhibitors of MMPs), with the appo-
sition of new extracellular matrix (ECM), in particular with the
production of Collagen type I (COL-I) (the principal constituent
of collagen fibrils), decorin, biglycan, versican, scleraxis,
tenascin C and aggrecan (constituents of ECM) by
tenocytes.2,9,15,18e21 Mechanical loads play a key role in the
maintenance of tissue homeostasis22: sedentary individuals
present high levels of pro-inflammatory cytokines, such as
TNF-a, IL-1b and VEGF, and low levels of COL-I, which improve
the state of inflammation and prelude to an increased activity
of MMPs (MMP-2, -9, -13) with a degenerative response and an
higher risk of tendon rupture.14 Without initial inflammation,
the healing process and the subsequent changes that char-
acterize chronic tendinopathies (>12 weeks) can not take
place.16
Early tendinopathy: the role of inflammation
Inflammation may play a role in the early initiation of tendon
pathologies.23 It has been hypothesised that inflammation
begins earlier than fibrotic and other degenerative tendon
changes.17 Tendon injuries are accompanied by inflamma-
tion, with endogenous expression of various mediators of
inflammation by tenocytes, including pro-inflammatory and
anti-inflammatory cytokines, and some Growth Factors, such
Please cite this article in press as: D'Addona A, et al., Inflammation in tendinopathy, The Surgeon (2017), http://dx.doi.org/10.1016/
j.surge.2017.04.004
as TNF-a, IL-1b, IL-6, IL-10, VEGF, TGF-b,10,23e25 COX-2
expression andPGE2 production.12,13,26 Among the pro-
inflammatory cytokines, TNF-a and IL-1b are the most
potent inducers of chemokines.27 Repetitive mechanical
overloading and hypoxic injury have long been suggested as
the main causes of tendinopathy, leading to elevated inflam-
matory markers.10,28 Repetitive mechanical overloading, in
particular, leads to elevated inflammatory markers such as
PGE2, IL-1b and TNF-a.15 Furthermore, various intracellular
stressors, both physiological and pathological, induce the
activation of NF-kB.29 In the acute phase of the inflammation
response, these cytokines are synthesised by a variety of cells
including lymphocytes, monocytes and endothelial cells.24
This involves tenocytes in the secretion of pro-inflammatory
cytokines in the early phases of inflammation, with a posi-
tive feedback, resulting in edema and hyperemia, detectable
in this phase only using US.1,14The reason why tendinopathy
will become chronic is still debated, but injuries, repeated
mechanical stresses and hypoxia seem to predispose to
chronicity.5 Increased oxygen demand by tenocytes during
overload, coupled with individual susceptibility, cause a state
of hypoxia that produces free radicals (ROS),6 one of the most
important immunogenetic stimulants, and the release of
VEGF.10,30
The role of IL-1 family
The family members of IL-1 are considered the most potent
cytokines produced by innate immunity.31 This family is
composed of IL-1a, IL-1b, IL-1829,31 and IL-33.10,25 Both IL-1a
(IL-1F1) and IL-1b (IL-1F2) are synthesized as precursor, and
they are cleaved respectively by Calpain10,30 and Caspase 1 (IL-
1b converting enzyme).32 The intracellular signaling involves
adapter proteins MyD88 (myeloid differentiation factor 88),
IRAK (IL-1-receptor-associated-kinase) and TRAF6 (TNF-re-
ceptor associated factor 6), and leads to the activation of NF-
kB, JNK (c-Jun N-terminal-kinase) and MAPK.31 Necrosis cau-
ses release of alarmins, such as IL-1a and IL-33, that, by
binding to different receptors of NF-kB, enhance the inflam-
matory response.10 NF-kB activation regulates the expression
of more than 500 different gene products linked with inflam-
mation, tumor cell transformation, survival, proliferation,
invasion, angiogenesis, metastasis and chemoresistance.11 IL-
1a and IL-33 are currently considered classical cytokine alar-
mins.10 Alarmins are the equivalent of damage-associated
molecular patterns (DAMPs), but are endogenous molecules
found in a variety of organelles in all cell types studied, and
maintain normal cell homeostasis.10,31 Currently, alarmins
include defensins, cathelicidins, eosinophil-associated ribo-
nucleases, HMGB (high mobility group box-1) proteins, gran-
ulysin, and iron-binding proteins (e.g. lactoferrin).31 An
alarmin is released rapidly during necrosis, is sequestered in
apoptosis, has potential for active secretion by immune cells,
and ultimately promotes homeostasis.10 IL-1a affects inflam-
matory and immune responses, angiogenesis and haemato-
poiesis.10 IL-33 (IL-1F11), a cytokine associated with Th2
response, is preferentially expressed in vascular endothelial
cells, with constitutive expression also in epithelial surfaces
and lymphoid organs.31 The increase of mRNA level of IL-33 in
tenocytes in vitro seems to be an important early signal in
 t h e s u r g e o n x x x ( 2 0 1 7 ) 1 e6 3

stressed tendon.10 IL-1b is a potent pro-inflammatory cytokine

present in markedly increased quantities in the synovium,
where it enhances inflammatory reactions in injured
joints,9,31 and contributes to the initiation of subsequent
proliferative and degenerative tendon changes.17 The actions
of this cytokine include local effects on the endothelium,
inducing systemic acute phase reactions and noxious effects
on tenocytes. IL-1b acts through its specific receptor, which is
shown to be present in tenocytes, the occupation of which can
activate numerous signaling pathways, including MAPKs.9 IL-
1b can induce inflammatory mediators such as COX-2, PGE2,
and the matrix-degrading enzymes MMPs.9 This cytokine is
able, on its own, to induce mRNA expression of MMP-1, -3,-8
and -13 in tendons cells,9,22,32 which may accelerate tendon
matrix degeneration.9 IL-1b enhances the expression of
prostaglandin E synthase (mPGES), which catalyzes the final
step in the conversion of PGH2 to PGE2.9,26 IL-1b also selectively
stimulates the expression of EP4 receptor (a G-protein coupled
receptors of PGE2) in human tenocytes.9 Potentially, the spe-
cific up-regulation of EP4 receptors in tenocytes by inflam-
matory cytokines may enhance inflammatory signaling
pathways, ultimately leading to tendon matrix degradation
and thus tendinopathy.9 IL-1b significantly downregulates the
expression of collagen type I at the mRNA level in human
tenocytes which may lead to the reduced deposition of ECM
during tendinopathies.9 Furthermore, IL-1b facilitates the
release of Substance P, contributing to inflammations with
nociceptive response with tendinopathies.17 These evidences
Fig. 1 e The IL-1 family. IL-1a, IL-1b and IL-33, with a
suggest that mechanical load, together with a release of in-
combinated signalling pathway through the activation of
flammatory cytokines, can initiate inflammation with subse-
MAPKs, stimulate mediators of inflammation causing
quent matrix destruction.22 (see Fig. 1).
insurgence of pain and ECM breakdown.

The role of IL-6

IL-6 is a pleiotropic cytokine produced mainly by monocytes/
macrophages and epithelial cells, but may also be induced in
endothelial cells and fibroblasts, bone marrow cells, neutro-
phils, mast cells or T- and B-cells.31 IL-6 is a dominant signal
seen in the circulation during and following stress conditions
such as hyperthermia.31,33 TNF-a and IL-1b promote the pro-
duction of IL-6, a cytokine with a central role in inflammation
and tissue injury.23,33 IL-6 induces the acute phase response
and enhances the healing phase.23 IL-6 is not only implicated
in inflammation, but also in the early phases of tendon heal-
ing, promoting the increase of COL1A1 expression in
tendons.23
The role of Heat Shock Proteins
Following oxidative and other form of stress, one family of
stress protein that is often upregulated is Heat Shock Proteins
(HSPs).32,34 HSPs play a protective role as molecular chaper-
ones in cells, facilitating the folding, intracellular transport,
assembly and disassembly of other proteins.32,34 Furthermore,
HSPs protect cells from oxidative damage and from necrosis
and apoptosis.34 They are potent activators of the innate im-
mune system, capable of inducing the expression of pro-
inflammatory cytokine.32,34 HSP 27 and the inducible HSP 70
are two main representatives of the HSP family modulated by
exercise-induced oxidative stress.32 Induction of HSPs in
response to stress serves to protect against the initial insult,
augment recovery, and produce a state of resistance to sub-
sequent stress in the cell. Over-expression of HSP 27 is
essential in preventing cells from undergoing apoptosis,
inhibiting specifically the cytochrome C and ATP-triggered
activity of Caspase 9 on the apoptotic pathway. HSP 27 also
indirectly modulates intracellular glutathione, which is also
regulated by exercise.32,34 HSP 70, instead, interacts with Apaf-
1 to prevent its interaction with the caspases preventing
apoptosis, protects cell from heat stress, from the cytotoxic
effect of TNF-a and from Nitric oxide (NO), induced by over-
expression of nitric oxide synthases.32 When the amount
and duration of mechanical load and the injurious stimuli
become too intense, tenocytes activate stress-activated pro-
tein kinases, which are oxygen free radicals and apoptotic
mediators, resulting in damage.32,34
Other cytokines
Many other cytokines are involved in this phase: IL-4, IL-
13,35 IL-8, a potent chemotactic agent and activator of neu-
trophils,10,16,36 IL-21 and its receptor, IL-21R.36 They are
important pro-inflammatory cytokines that act as an
angiogenetic factor in the first phases of inflammation.
Probably, these cytokines play a role in early tendino-
pathies. These effects on tenocytes include increased

Please cite this article in press as: D'Addona A, et al., Inflammation in tendinopathy, The Surgeon (2017), http://dx.doi.org/10.1016/
j.surge.2017.04.004
4 t h e s u r g e o n x x x ( 2 0 1 7 ) 1 e6
proliferation and collagen synthesis, increased collagenase
and protease synthesis, with increased synthesis of PGE2
with insurgence of pain.5,36 Furthermore, IL-4, IL-10, IL-13
(as in rheumatoid arthritis) and IL-15 are involved, espe-
cially in the healing stage.35,36 In particular, the expression
of IL-21R is regulated in early tendinopathy after stimula-
tion with TNF-a and IL-1b, as in Rheumatoid Arthritis,
where it has been shown that the IL-21/IL-21R axis is
involved in dysregulated MMPs production.36 The IL-21R has
two different binding sites: an alpha chain that links IL-21,
and a gamma chain that is common to different cytokines,
such as IL-15, IL-7 and IL-13.36 High levels of IL-4R and IL-
13R (except gamma chain) are found in tenocytes, and
probably they could be involved in the proliferation of these
cells, but not in collagen production, suggesting that these
two cytokines might facilitate tendon repair through their
tenoproliferative effects.35,36 (See Fig. 2).
The role of VEGF
VEGF (Vascular Endothelial Growth Factor) is released after
the hypoxic stress in earlier stages of the condition. It is the
principal factor responsible for neoangiogenesis, and, thanks
to it, inflammation mediators can reach the injured zone.
VEGF is activated by HIF-1a and HIF-1b heterodimer under
hypoxia stress condition.10,37 VEGF, with IL-6, IL-21R and
probably other cytokines such as IL-15, has the potential to
stimulate the expression of matrix metalloproteases with the
degradation of ECM, and inhibit the expression of matrix
Fig. 2 e IL-21 pathway. TNF-a and IL-1b induce the
expression of IL-21R, stimulating inflammation,
degradation of ECM, insurgence of pain and healing
processes.
Please cite this article in press as: D'Addona A, et al., Inflammation in tendinopathy, The Surgeon (2017), http://dx.doi.org/10.1016/
j.surge.2017.04.004
metalloproteases (TIMPS) in various cell types (e.g., teno-
cytes, fibroblasts, chondrocytes, endothelial cells). Therefore,
this cytokine may play a significant role in the pathogenetic
processes of degenerative tendon disease.30,36 With other
growth factors secreted by inflammatory cells, such as EGF,
FGF, TGF-b and IGF-1, VEGF promotes the proliferation of
tenocytes and the release of COX-2,PGE2 and prostacyclins
implicated in the insurgence of pain in acute
tendinopathy.12,13
The role of metalloproteinases
The MMPs involved in tendon damage are in particular MMP-
1, -2, -3, -8, -9, -13, -14,19,38 and their activation results from an
imbalance with their inhibitors, the TIMPs.2,4,19In particular,
TIMP-3 is the most important TIMP involved in the inhibition
of ADAMs (disintegrin and metalloproteinases) and ADAMTs
(ADAMs with thrombospondin motif).19,38 They play a central
role in matrix degeneration and pain regulation. MMP-1, -8
and -13 are involved in the disruption of COL1, COL2 and COL3;
MMP-18 (collagenase 4) is directed against COL IV; MMP-2 and
-9 degrade more little fragments of tendon while MMP-3 and
-10 (stromelysins) and MMP-7 (matrilysin) are involved in the
activation of other MMPs. Some MMPs, such as MMP-2, -3 and
-14, also mediate healing processes.19,38 An increase in net
MMP activity is likely to indicate matrix degradation, which
may represent part of the remodeling process in wound
healing.39
The role of PGE2, substance P and peroxiredoxin 5
COX-2, a major marker of tissue inflammation, converts
arachidonic acid (AA) into prostaglandins, such as PGE2.9,26
PGE2, one of the major mediators of pain and acute inflam-
mation in tendons and other tissues,9 is produced by teno-
cytes and other fibroblasts in response to injury and after
stimulation with pro-inflammatory cytokines, initiating MMP
mediated catabolism of tendon ECM5 and insurgence of
pain,2,4 mediating tendon inflammation.26 Both in vivo and
in vitro experimental models suggest that production ofPGE2
may play an important role in the development of tendinop-
athy.9 For example, in human tenocytes, repetitive mechani-
cal loading elevates the production of PGE2.9,12,13,40 The most
important catabolic functions of PGE2 in connective tissues
are inhibition of Collagen type I synthesis and induction of
MMPs.9 For instance, PGE2 upregulates MMP-1 an -3 gene and
protein expression.9 In healthy tissues, prostaglandins may
also have beneficial regulatory actions by maintaining normal
physiological processes such as local bone remodeling and
modification of renal blood flow.5 PGE2 levels decrease with
aging in normal tendons as a consequence of the reduction in
tendon cellularity.5 Substance P, another important pain
mediator in addition to PGE, regulates the expression of these
molecules, increasing the degradation of matrix.41 Substance
P has several roles, including facilitating histamine release
from mast cells and thus enhancing vasodilatation and
extravasation of immune cells.17 Another candidate impli-
cated in stress-induced tendinopathy is the antioxidant per-
oxiredoxin 5.2,4,25 Peroxiredoxin may play a role in protecting
against cellular damage.25
 t h e s u r g e o n x x x ( 2 0 1 7 ) 1 e6
Inflammation and healing
Healing of human tendons is lengthy.16 Tendon healing can be
schematically divided into 3 overlapping phases2,4,14,16: in-
flammatory, repairing and remodeling phases.2,4,16 (See Fig. 3).
In the initial inflammatory phase, which lasts about 24 h,
platelets and inflammatory cells (e.g.,: neutrophils, erythro-
cytes, monocytes and macrophages) migrate to the wound site,
and are responsible for the state of inflammation.2,4,12e14
Vasoactive and chemotactic factors are released with
increased vascular permeability, initiation of angiogenesis,
stimulation of tenocytes proliferation, and recruitment of
more inflammatory cells.2,4,14 Wounding and inflammation
provoke release of GFs and cytokines from platelets, poly-
morphonuclear leukocytes, macrophages, and other inflam-
matory cells.2,14 These growth factors induce
neovascularization and chemotaxis of fibroblasts and teno-
cytes, and stimulate their proliferation as well as synthesis of
collagen.2,14 The best documented of these factors are growth
and differentiation factors (GDFs) and Scleraxis (Scx).2,4,14 In
particular, Scx regulates the expression of the gene COL1A1 in
tenocytes.14 Tenocytes gradually migrate to the wound, and
type III collagen synthesis is initiated.2,4 This phase is followed
by the remodeling stage.2,4 Synthesis of type III collagen peaks
during this stage, which lasts for a few weeks.4 After about 6
weeks, the modeling stage starts.2,4 The modeling phase can be
divided into a consolidation and maturation stage.4 A higher
proportion of type I collagen is synthesized during this stage.4
Cytokines are released during the inflammatory healing
phase.16 TNF-a, IL-1b, IL-6 and IL-8 exert pro-inflammatory
Fig. 3 e An illustrated scheme of healing process of
tendons.
Please cite this article in press as: D'Addona A, et al., Inflammation in tendinopathy, The Surgeon (2017), http://dx.doi.org/10.1016/
j.surge.2017.04.004
5
actions, and IL-6, IL-8 and IL-10 have anti-inflammatory
effects.16 IL-6 may serve a dual role as an anti-
inflammatory cytokine and as a promoter of collagen syn-
thesis16,23: it plays a major role in stimulating tendon
collagen synthesis, in particular COL1A1,23 and has inhibi-
tory effects on TNF-b and IL-1b,16,24 with activation of IL-10
transcription/translation/expression/release, and expres-
sion of IL-1 receptor antagonist.16 IL-10 inhibits the
expression of several pro-inflammatory cytokines, including
IL-1, IL-2 and TNF-a.16 IL-8 works primarily as a chemokine,
hence the alternative name CXCL8, whose main role is to
attract neutrophils to the site of injury.16 IL-8 may stimulate
angiogenesis, which may plausibly and essentially affect the
tendon repair process.16 Whether cytokines are present and
play an inflammatory or callus-promoting role in the early
proliferative phase of in vivo human tendon tissue healing is
presently unclear.16 MMPs and metalloproteinases with
thrombospondin motifs (ADAMTs) are important regulators
of ECM network remodeling, and their levels are altered
during tendon healing.2,4,14,19,20 MMP-9 and MMP-13 mediate
tissue degradation during the early phase of healing,
whereas MMP-2, -3 and -14 mediate both tissue degradation
and later remodeling.2,4,14,19,20 Healing failure, from
extrinsic and intrinsic factor, will induce the failed healing
response, typical of tendinopathy.1,7,14,18,20 Furthermore,
Nitric oxide (NO) is also involved in the healing process.2,4,14
It is synthesized from L-arginine by a family of enzymes, the
nitric oxide synthases (NOSs).2,4,14 NO favors the healing
process by increasing collagen synthesis, with high levels of
NOS after 7 days.2,4,14,25 Furthermore, overexpression of
inducible nitric oxide synthase in human tenocytes stimu-
lates transcription and translation of a number of ECM-
related genes, such as collagen I, II and IV; biglycan,
decorin, laminin and MMP-10.25
Conclusions
Inflammation plays an important role in the pathogenesis of
tendon pathologies, in particular before clinical evidence of
the condition, when inflammatory cells and mediators are
strongly involved. It is still not clear what causes the onset of
early tendinopathy, and how it may evolve into a full-blown
tendinopathy. The increasingly important role of inflamma-
tion with all its mediators could make possible to formulate an
early diagnosis of tendinopathy. The future challenge would
be to study more timely treatment, without resorting to sur-
gery, and to prevent tendon ruptures.
Competing interests
Authors have no financial competing interests to disclose.
Acknowledgments
We want to acknowledge all the persons who contributed to
the writing of this review.
6 t h e s u r g e o n x x x ( 2 0 1 7 ) 1 e6

references 20. Jones ER, Jones GC, Legerlotz K, Riley GP. Cyclical strain
modulates metalloprotease and matrix gene expression in
human tenocytes via activation of TGF-b. Biochim Biophys acta
2013:2596e607.
1. Kaux J-F, Forthomme B, Le Goff C, Crielaard J-M, Croisier J-L.
21. Corps AN, Robinson AH, Movin T, Costa ML, Hazleman BL,
Current opinions on tendinopathy. J sport Sci Med
Riley GP. Increased expression of aggrecan and biglycan
2011;10:238e53.
mRNA in Achilles tendinopathy. Rheumatology 2006;45:291e4.
2. Sharma P, Maffulli N. Tendon injury and tendinopathy:
22. Wang James H-C, Thampatty BP, Lin J-S, Im H-J.
healing and repair. JBJS 2005;87:187e202.
Mechanoregulation of gene expression in fibroblasts. Gene
3. van Dijk CN, van Sterkenburg MN, Wiegerinck JI, Karlsson J,
2007;391:1e15.
Maffulli N. Terminology for Achilles tendon related disorders.
23. Legerlotz K, Jones ER, Screen HR, Riley GP. Increased
Knee Surg Sports Traumatol Arthrosc 2011;19:835e41.
expression of IL-6 family members in tendon pathology.
4. Sharma P, Maffulli N. Biology of tendon injury: healing,
Rheumatology 2012;51:1161e5.
modeling and remodeling. J Musculoskelet Neuronal Interact
24. Al-Sadi O, Schulze-Tanzil G, Kohl B, Lohan A, Lemke M,
2006;6(2):181e90.
Ertel W, et al. Tenocytes, pro-inflammatory cytokines and
5. Dakin SG, Dudhia J, Werling NJ, Werling D, Abayasekara DRE,
leukocytes: a relationship? MLTJ 2011;1(3):68e76.
Whealands Smith RK. Inflamm-aging and arachidonic acid
25. Chaudhury S, Carr AJ. Lessons we can learn from gene
metabolite differences with stage of tendon disease. PLos One
expression patterns in rotator cuff tears and tendinopathies. J
2012;7(11).
Shoulder Elb Surg 2012;21:191e9.
6. Yao L, Bestwick CS, Bestwick LA, Aspden RM, Maffulli N. Non-
26. Yang G, Im H-J, Wang James H-C. Repetitive mechanical
immortalized human tenocyte cultures as a vehicle for
stretching modulates IL-1b induced COX-2, MMP-1
understanding cellular aspects to tendinopathy. Transl Med @
expression, and PGE2production in human patellar tendon
UniSa 2011;1(1):173e94.
fibroblasts. Gene 2005;363:166e72.
7. Maffulli N, Ewen SW, Waterston SW, Reaper J, Barrass V.
27. Brabcova E, Kolesar L, Thorburn E, Striz I. Chemokines
Tenocytes from ruptured and tendinopathic Achilles tendon
induced in human respiratory epithelial cells by IL-1 family of
produce greater quantities of type III collagen than tenocytes
cytokines. Folia Biol 2014;60:180e6.
from normal Achilles tendon: an in vitro model of human
28. Neviaser A, Andarawis-Puri N, Flatow E. Basic mechanisms
tendon healing. Am J Sports Med 2000;28:499.
of tendon fatigue damage. J Shoulder Elb Surg
8. Po-Yee Pauline, Chan Lui Lai-Shan, Lee Yuk-Wa, Fu Sai
2012;21:158e63.
Chuen, Chan Kai-Ming. Sustained expression of
29. Hayden MS, Ghosh S. Signaling to NF-kB. Genes Dev
proteoglycans and collagen type III/type I ratio in a calcified
2004;18:2195e224.
tendinopathy model. Rheumatology 2010;49:231e9.
30. Oliva F, Barisani D, Grasso A, Maffulli N. Gene expression
9. Thampatty BP, Li H, Im H-J, Wang James H-C. EP4 receptor
analysis in calcific tendinopathy of the rotator cuff. Eur Cells
regulates collagen type-I, MMP-1, and MMP-3 gene expression
Mater 2011;21:548e57.
in human tendon fibroblasts in response to IL-1b treatment.
31. Striz I, Brabcova E, Kolesar L, Sekerkova A. Cyotkine
Gene 2007;386:154e61.
networking of innate immunity cells: a potential target of
10. Millar Neal L, Murrel George AC, McInnes Iain B. Alarmins in
therapy. Clin Sci 2014;126:593e612.
tendinopathy: unraveling new mechanism in a common
32. Millar NL, Murrell GAC. Heat Shock proteins in tendinopathy:
disease. Rheumatology 2013:1e11.
novel molecular regulators. Mediat Inflam 2012:1e7.
11. Buhrmann C, Mobasheri A, Busch F, Aldinger C, Stahlmann R,
33. Welc Steven S, Clanton Thomas L. The regulation of IL-6
Montaseri A, et al. Curcumin modulates nuclear factor kb-
implicates skeletal muscle as an integrative stress sensor and
mediated inflammation in human Tenocytesin vitro: role of
endocrine organ. Exp Physiol 2013;98(2):359e71.
the phosphatidylinositol 3dkinase/Akt pathway. J Biol Chem
34. Millar NL, Wei AQ, Molloy T, Bonar F, Murrell GAC. Heat Shock
2011;286:28556e66.
protein and apoptosis in supraspinatus tendinopathy. Clin
12. Del Buono A, Battery L, Denaro V, Maccauro G, Maffulli N.
Orthop Relat Res 2008;466:1569e76.
Tendinopathy and inflammation: some truths. Int J
35. Courneya J-P, Luzina IG, Zeller CB, Rasmussen JF, Bocharov A,
Immunopathol Pharmacol 2011;24(1 Suppl 2):45e50.
Schon LC, et al. Interleukins 4 and 13 modulates gene
13. Battery L, Maffulli N. Inflammation in overuse tendon
expression and promote proliferation of primary human
injuries. Sports Med Arthrosc 2011;19(3):213e7.
tenocytes. Fibrogenes Tissue Repair 2010;3:9.
14. Abate M, Gravare-Silbernagel K, Siljeholm C, Di Iorio A, De
36. Campbell AL, Smith NC, Leach WJ, Fazzi UG, Rooney BP,
Amicis D, Salini V, et al. Pathogenesis of tendinopathies:
Reilly JH, et al. IL-21 receptor expression in human
inflammation or degeneration? Arthritis Res Ther 2009;11:235.
tendinopathy. Mediat Inflamm 2014;2014.
15. Killian Megan L, Cavinatto Leonardo, Galatz Leesa M,
37. Liang M, Cornell Hannah R, Baboldashti NZ, Thompson MS,
Thomopoulos Stavros. The role of mechanobiology in tendon
Carr Andrew J, Hulley PA. Regulation of Hypoxia-induced cell
healing. J Shoulder Elb Surg 2012;21:228e37.
death in human tenocytes. Adv Orthop 2012;2012:12. Article ID
16. Ackermann PW, Domeij-Arverud E, Leclerc P, Amoudrouz P,
984950.
Nader GA. Anti-inflammatory cytokine profile in early human
38. Visse R, Nagase H. Matrix metalloproteinases and tissue
tendon repair. Knee Surg Sports Traumatol Arthrosc
inhibitors of metalloproteinases. Circ Res 2003;92:827e39.
2013;21:1801e6.
39. Riley Graham P, Curry V, DeGroot J, van El B, Verzijl N,
17. Fedorczyk Jane M, Barr Ann E, Rani Shobha, Gao Helen G,
Hazleman BL, et al. Matrix metalloproteinase activities and
Amin Mamta, Amin Shreya, et al. Exposure-dependent
their relationship with collagen remodelling in tendon
increases in IL-1b, substance P, CTGF,and Tendinosis in flexor
pathology. Matrix Biol 2002;21:185e95.
digitorum tendons with upper extremity repetitive strain
40. Khan MH, Li Z, Wang JH. Repeated exposure of tendon to
injury. J Orthop Res 2010;28:298e307.
PGE2leads to localized tendon degeneration. Clin J Sports Med
18. Karousou E, Ronga M, Vigetti D, Passi A, Maffulli N. Collagens,
2005;15:27e33.
proteoglycans, MMP-2, MMP-9 and TIMPs in human Achilles
41. Riley G. The pathogenesis of tendinopathy. A molecular
tendon rupture. Clin Orthop Relat Res 2008;466:1577e82.
perspective. Rheumatology 2004;43:131e42.
19. Maffulli N, Oliva F, Del Buono A, Osti L. Metalloproteases and
tendinopathy. MLTJ 2013;3(1):51e7.

Please cite this article in press as: D'Addona A, et al., Inflammation in tendinopathy, The Surgeon (2017), http://dx.doi.org/10.1016/
j.surge.2017.04.004