tendinopatia

Prévia do material em texto

Inflammation in Overuse Tendon Injuries
Lucy Battery, BSc, Hons and Nicola Maffulli, MD, MS, PhD, FRCS(Orth)
Abstract: Overuse tendon injuries present with pain and swelling
of the affected tendon with associated decrease in exercise
tolerance and function of the limb. After early inflammatory
and degenerative hypotheses, the term “tendinopathy” is now
deemed a more appropriate reflection of the mixed histopatho-
logical picture seen in operative biopsies from affected patients.
The condition presents histopathological evidence of “failed
healing response,” but its etiology remains unclear. The
incidence of tendinopathy is increased in individuals with
obesity and decreased insulin sensitivity (as seen in type 1 and
type 2 diabetes mellitus). These groups of patients also exhibit
an increased risk of developing a state of chronic low-grade,
systemic inflammation. This paper considers the theoretical
bases to discuss whether these conditions may predispose to the
development of tendinopathy and the implication that such a
relationship may have on its management.
Key Words: tendinopathy, failed healing response, risk factors,
chronic inflammatory state, obesity, decreased insulin sensitiv-
ity, future management
(Sports Med Arthrosc Rev 2011;19:213–217)
Overuse tendinopathy presents with pain and swellingof the affected tendon with associated decrease in
exercise tolerance and function of the limb.1–3 Early authors
hypothesized the condition to be the result of inflammatory
changes within the tendon and its adnexae, secondary to its
frequent or excessive use, assigning the label of “tendinitis”
or “tendonitis” to such a presentation.1–4
However, as evidence mounted that anti-inflamma-
tory agents were largely unsuccessful in treating the
condition,4,5 coupled with increasing histopathological
data showing evidence of degenerative change but little
inflammation, the inflammatory basis in overuse tendon
injury became decreasingly popular.3,5–8 The term
“tendonitis” became increasingly replaced by that of
“tendinosis,”8 but a definitive diagnosis of either should
only be made following histopathological confirma-
tion.5,7,8
However, it was soon highlighted that tendon biopsies
from operated patients were likely to represent the end
stage of a pathological continuum,3 likely demonstrating a
very histopathological picture to that which would be seen
in the initial stages of injury.6–8 This was supported by
evidence from human and animal biopsies that revealed that
both peritendinitis and a failed healing response labeled
“tendinosis” could be present concurrently.8
The term “tendinopathy” was therefore deemed a
more appropriate reflection of this variability,3 and
coincided with the most recent “failed healing response”
hypothesis for overuse tendon injury.2,3,5–7,9 The “failed
healing response” model suggests that, after an acute
insult to the tendon, an early inflammatory response that
would normally result in successful injury resolution
instead undergoes progressive degeneration secondary to
an ineffective healing response.2,5–7
If accepted, this model begs the question of why the
healing response is successful in some individuals but fails in
others. More importantly, can we identify factors that may
increase the risk of this ineffective healing response, and, by
so doing, initiate measures to prevent the degenerative
change noted in end stage tendinopathy problems?
The incidence of tendinopathy is increased in
individuals with obesity and decreased insulin sensitivity,
as seen in type 1 and type 2 diabetes mellitus ( T1/
T2DM).3,10–13 As these individuals also exhibit an
increased risk of developing a state of chronic low-grade,
systemic inflammation,11–16 it may be possible that such a
state may predispose to the development of tendinopathy
in these individuals.
INFLAMMATION IN OBESITY
Evidence for a chronic, low-grade inflammatory
state in obesity is represented principally by marked
increases in plasma levels of proinflammatory cytokines
such as tumor necrosis factor (TNF)-a and interleukin
(IL)-6, and proinflammatory chemokines such as mono-
cyte chemoattractant protein (MCP)-1.12
Macrophages and other immune cells are also
derived from adipose tissue, and an intricate relationship
exists between them and the adipocyte-derived proin-
flammatory cytokines. In particular, MCP-1 induces
macrophage infiltration of adipose tissue. In turn,
activated macrophages release additional proinflamma-
tory cytokines: notably, TNF-a expression is significantly
increased.13 This reduces the expression of adiponectin,
an adipocyte derived anti-inflammatory hormone.Copyright r 2011 by Lippincott Williams & Wilkins
From the Centre for Sports and Exercise Medicine, Queen Mary
University of London, Barts and The London School of Medicine
and Dentistry, Mile End Hospital, London, England.
The authors declare no conflict of interest.
Reprints: Nicola Maffulli, MD, MS, PhD, FRCS(Orth), Centre for
Sports and Exercise Medicine, Queen Mary University of London,
Barts and The London School of Medicine and Dentistry, Mile End
Hospital, 275 Bancroft Road, London E1 4DG England (e-mail:
n.maffulli@qmul.ac.uk).
REVIEW ARTICLE
Sports Med Arthrosc Rev � Volume 19, Number 3, September 2011 www.sportsmedarthro.com | 213
This altered balance between chemotactic mediators
and macrophages results in a state of persistent local
inflammation within the adipose tissue.11
Moreover, increased adipose mass index alters the
relationship between leptin and suppressor T cells.
Leptin, an adipocyte-derived hormone responsible for
the central control of energy balance, also seems to inhibit
the proliferative capacity of suppressor T cells.14 In
obesity, a correlated rise in leptin levels is observed as
adipocyte numbers increase, with subsequent increased
inhibition of suppressor T-cell function. This state is then
further worsened by the tropism that suppressor T cells
exhibit for adipocytes, particularly as their numbers
increase in obesity. As a result, progressively less
suppressor T cells become available in the systemic
circulation with time.14
The increased presence of T suppressor cells in
adipose tissue also, however, up-regulates local produc-
tion of other adaptive immune system products while also
adding to the aforementioned activation of macrophages
and other innate immune system components such as
mast cells.13 This provides further reinforcement for a
state of sustained inflammation.
Finally, expansion of adipose tissue results in an
increase in the number of blood vessels and connective
tissue fibroblasts found within the tissue itself, providing
further evidence that it is experiencing active inflamma-
tion.13
INFLAMMATION IN STATES OF IMPAIRED
INSULIN SENSITIVITY
Patients with type 1 and type 2 diabetes exhibit a
less effective healing response, but the reason for this had
until recently been unclear.16
In particular, any investigation as to whether a
chronic inflammatory state similar to that witnessed in
obesity may be implicated was deemed highly proble-
matic, as the raised plasma levels of proinflammatory
cytokines and chemokines found in obesity induce both
local and systemic insulin resistance, thus predisposing to
the development of type 2 diabetes.16
Recently, however, it has been demonstrated that
the presence of an independent relationship between
impaired insulin sensitivity and the development of
chronic low-grade inflammation through the discovery
of the effect that insulin has on a protein called FOXO1.16
FOXO1 is a key up-regulator of the proinflammatory
cytokine IL-b, but its levels are normally physiologically
inhibited by insulin.
Although initially in type 2 diabetes insulin levels are
either normal or high, when the pancreas is no longer able
to compensate for the systemic state of increased insulin
resistance, its endogenous production begins to decrease,17
thus resulting in increased expression of FOXO1 and,
subsequently, IL-b.16 Conversely, IL-b disrupts insulin
signaling, suggesting that inflammationand insulin resis-
tance may positively reinforce each another.16
INFLAMMATION IN EARLY TENDINOPATHY
After acute injury, tendons typically undergo 3
distinct healing phases.1 In the first few days postinjury,
the tendon enters a state of acute inflammation, with
invasion of inflammatory cells, including monocytes and
macrophages, enabling phagocytosis of necrotic debris.1
This phase is followed by a “proliferative phase”
that persists for roughly 3 weeks postinjury. In response
to proinflammatory cytokines,18 fibroblasts produce a
new type 1 collagen both within the tendon and its
extracellular matrix, progressively increasing the tendon’s
strength.11,12 Vascular endothelial growth factor is also
released, thus facilitating neovascularization12 and sub-
sequent granulation tissue formation.11,12 Accordingly,
pain is frequently noted in this stage, and may be
continuous, intermittent or activity related.12
The final phase of tendon healing involves the
maturation and remodeling of this collagen, coupled with
decreased cellularity and vascularity in the area; a long
process, taking up to an year to complete even under
optimal healing conditions.19 In addition, even if com-
plete histopathological healing is achieved, the tendon
will usually remain less resistant to the mechanical strain
placed upon it in the future.1,14
DISCUSSION
Considering the influence that a prolonged state of
low-grade systemic inflammation may have on the healing
process after acute tendon injury, it must be appreciated
that tendon healing is a delicate and prolonged process
even under optimal physiological conditions.3,12,19
Even a minor disruption to any of the noted healing
stages could result in a much more prolonged and
complicated resolution of injury. Similarly, if several
minor disruptions to this process occur (in the form of
“microtraumas”), the prospect of complete healing and
resolution of injury becomes progressively unlikely.3
Therefore, it may be possible that a systemic state of
chronic, low-grade inflammation may act as a prolonged
disruptor of tendon healing. This question may be
considered by examining the influences that such a state
may have on the various components of the recognized
healing process that tendons normally exhibit after an
acute injury.
The acute inflammatory phase noted in the first few
days after tendon injury is marked by the invasion of
inflammatory cells such as macrophages and monocytes.8
As the chronic inflammatory state witnessed in obesity is
correlated with a reduction in the numbers of circulat-
ing macrophages,11 it is possible that such a decrease in
the availability of circulating cells would result in the
mounting of a lesser effective early healing response.
Interestingly, Millar et al,20 examining the histo-
pathological state of full thickness tears of the supraspi-
natus tendon, found that inflammatory cell infiltrates in
such samples correlated inversely with the size of the tear
seen, and that large tears in particular showed a marked
reduction in all cell types. In contrast, M2 macrophages as
Battery and Maffulli Sports Med Arthrosc Rev � Volume 19, Number 3, September 2011
214 | www.sportsmedarthro.com r 2011 Lippincott Williams & Wilkins
well as mast cells were notable in samples that exhibited
increased fibroblast cellularity.20
M2 macrophages are responsible for dampening the
inflammatory response, resolving necrotic debris and
promoting the angiogenesis that occurs in the proliferative
phase of tendon healing.20 Such findings are consistent with
a postinjury state of “failed healing,” in which evidence of
matrix disorganization, increased amounts of extracellular
ground substance and a degree of separation between
collagen fibers has been noted,18,19 with associated greater
vulnerability to future mechanical strain.3
This relationship may also help to explain the
influence that mechanical overuse plays in the develop-
ment of tendinopathy. For example, Mavrikakis et al,21
examining the incidence of tendinopathy among patients
with type 2 diabetes, discovered that unilateral or
bilateral tendinopathy was found in 32% of the diabetic
patients studied versus 10% of controls. Also, when the
incidence of unilateral tendinopathy among the diabetics
was examined more closely, 45% were found to occur in
the right shoulder compared with just 27% in the left
shoulder.11
However, a lack of exposure to adequate levels of
physiological stress over a prolonged time period or
“underloading” may paradoxically predispose to overload
injury.12 An underloaded tendon may become unable to
cope with increased demands imposed on it. Thus,
underuse of a tendon may result in an imbalance between
matrix metalloproteinases and their inhibitors (tissue
inhibitors of matrix metalloproteinases), with resultant
tendon degradation.12
Therefore, although the traditional theory of
mechanical overuse is not the sole cause of tendinopathy,
it may predispose to its development by increasing the
mechanical strain on an already weakened tendon.3,12
Acute tendon rupture may in effect simply represent the
straw (mechanical trauma) that broke the camel’s back.5
Such a pattern of repetitive microtrauma would also be
consistent with the known positive correlation between
increasing age and athletic activity levels and incidences
of tendinopathy.3
The finding of a decreased presence of mast cells in
the aforementioned biopsies from large supraspinatus
tears is also noteworthy.20 Mast cells are important to
tendon healing, particularly in the later (proliferative and
reparative) healing phases, where they have been shown
to be responsible for the release of several profibrotic
factors such as transforming growth factor (TGF)-b and
IL-1 and IL-4.22 They also actively secrete mast-cell
tryptase, which in turn triggers proteinase-activated
receptor-2 production.22 Proteinase-activated receptor-2
subsequently induces a cyclooxygenase (COX)-2-depen-
dent proliferative and fibrotic response among tendon
fibroblasts.22
The contribution of TGF-b is of particular interest,
as its role as a profibrotic factor has been positively
associated with the pathophysiology of scleroderma and
other autoimmune conditions characterized by the
inappropriate formation of fibrotic tissue.23,24 Known to
be the most potent stimulator of myofibroblasts, as well
as to up-regulate the production of other profibrotic
cytokines, the expression of TGF-b is consistently raised
in biopsies from scleroderma patients.15 Conversely,
inhibition of some of the profibrotic cytokines whose
production is stimulated by TGF-b eliminates the
expression of collagen I and III in scleroderma cells.23
As such, if TGF-b production were reduced
secondary to a reduction in mast cell numbers, it is easy
to imagine the detrimental effect that this could have on
tendon healing, especially if the production of type I and
III collagen is also reduced.15 Operative biopsies taken
from patients with chronic tendinopathy consistently
demonstrate a loss of the normal “bundled” appearance
of collagen.25,26
Studies of patients with scleroderma suggests that
cytokines such as TNF-a can have both angiogenic and
angiostatic effects depending on the duration of their
presence.23 Moreover, fibrotic changes can also result
from extracellular matrix changes without the presence of
a concurrent inflammatory response; thus providing a
possible explanation for the known lack of efficacy of
anti-inflammatory agents in the management of patients
with scleroderma.15,16
Given the lack of efficacy of anti-inflammatory agents
coupled with the mixed histopathological picture of both
inflammatory and degenerative changes noted in operative
biopsies,1 it seems sensible to consider that an atypical
relationship may also exist between inflammation and the
failed healing response changes seen in chronic tendino-
pathy; and that a background state of chronic, low-grade
inflammation may predispose and/or exacerbate this.
The chronic inflammatory state in obesity results in
the migration of immune cells such asmacrophages and
mast cells into adipose tissue.11–14 This is correspondingly
associated with a decrease in the circulating levels of those
cells. This decreased availability of circulating immune cells
may mean that the immune response to acute tendon injury
would be intrinsically less effective. This hypothesis may
account for the aforenoted13 reduced levels of macrophages
and mast cells in high grade supraspinatus tears.
Examining the proinflammatory cytokine release
that marks both the acute inflammatory and (early)
proliferative phase of tendon healing,11,12 could a chronic,
low-grade inflammatory state also affect the role of these
healing mediators?
The exogenous administration of the prostaglandins
PGE1 and PGE2 can actively induce tendon changes
consistent with the development of tendinopathy.27 Sullo
et al27 injected PGE1 peritendinously, and found the
tendons to be pathologically thickened by a mean of
134.1% at 1 week postinjection, and remained thickened
(though to a lesser extent: 125.7%) at the study end point
some 4 weeks later.
Cilli et al28 investigated the effects of PGE2 on
human patellar fibroblasts demonstrating that its exo-
genous administration resulted in decreased fibroblast
proliferation as well as a subsequent decrease in collagen
synthesis. As the production of adequate collagen is
Sports Med Arthrosc Rev � Volume 19, Number 3, September 2011 Inflammation in Overuse Tendon Injuries
r 2011 Lippincott Williams & Wilkins www.sportsmedarthro.com | 215
essential for successful tendon healing, raised levels of
PGE2 in vitro could well contribute to a failed healing
response through disorganization and degeneration of the
cellular matrix.
Postinjury tendon inflammation results in marked
increases in PGE2 and the leukotriene LTB4, and previous
studies have suggested that raised levels of both of these
factors are implicated in the pathogenesis of tendino-
pathy.29 Nevertheless, the in vivo scenario may be more
complicated.30 Although high doses of LTB4 greatly
enhanced the catabolic effect of PGE2 on fibroblasts, low
doses of LTB4 seemed to actually counterbalance the
same effect. Therefore, the ability of LTB4 to counteract
PGE2 may be important in delaying the development of
tendinopathy.30
The persistently raised levels of PGE2 and LTB4
noted in obesity and states of impaired insulin sensitivity
would mean that the balance between these factors would
impair successful healing after an acute tendon injury.
Fu et al31 found elevated expression of PGE2 in
chronic patellar tendinopathy, along with marked ex-
pression of COX-2 and TGF-b1. COX-2 is induced by
proinflammatory cytokines in the active inflammatory
phase that follows tendon injury but, under normal
conditions, its presence diminishes as when active
inflammatory phase ends.31 However, COX-2 can also
act as an inducer of PGE2 resulting in further inflamma-
tion if its presence persists.31 These findings may be
consistent with an abnormal resolution of the inflamma-
tory response to acute tendon injury that then resulted in
sustained expression of inflammatory mediators.31 The
presence of these mediators causes the clinical signs of
swelling, tenderness, and activity-related pain typically
found in patients with tendinopathy.31
Considering all of the above, it is possible that a
chronic low-grade inflammatory state may predispose
and contribute to the failed healing response implicated in
the development of tendinopathy.
However, if this is the case, what impact may this
have on the future management of tendinopathy, in
particular in those known to have comorbid obesity and/
or decreased insulin sensitivity? Moreover, could early
intervention in these “high-risk” populations actually
prevent the development of tendinopathy?
Roth et al13 suggested that successful lifestyle
intervention can significantly reverse the systemic inflam-
matory state found in obesity. Similarly, dietary changes
may have a notable role in improving symptomatic
tendinopathy.18,32
Conversely, there is some suggestion that the
complications of systemic inflammation may actually
increase with increasing obesity levels. For example, the
risk for surgery for rotator cuff tendinopathy was
positively correlated with increasing body mass index
(BMI), with men of BMI of 25 to <30 having an odds
ratio (OR) of 1.25 for shoulder surgery, with this risk
rising to an OR of 2.93 for men of BMI of Z35.15 Similar
ORs were also noted in female patients of these BMI
groups.15
Similarly, in a study examining the nature of upper
limb musculoskeletal problems in diabetic patients, those
with poorer metabolic control [indicated by increased
glycosylated hemoglobin (HbA1c) levels], were more
likely to report an upper limb musculoskeletal problem
and more likely to complain of pathology at multiple
sites. They were also found, as might be expected, to have
more diabetic complications affecting other systems.10
Longo et al33 also recently demonstrated that
individuals with higher fasting plasma glucose levels
within the normoglycemic range demonstrated a higher
incidence of rotator cuff tears (P=0.007) than those with
meniscal tears. The attachment of free glucose molecules
to collagen results in altered collaged solubility, increased
resistance to enzymatic degradation, and impaired cross-
linking.27 This impaired cross-linking may well underlie
many diabetic complications.27 Therefore, increased
plasma glucose levels may hinder the successful formation
of collagen after acute tendon injury, and thus contribute
to the subsequent development of chronic tendinopathy
secondary to a failed healing response.27
The above findings highlight the difference that
basic interventions, such as weight loss and good diabetic
control, among these “high risk” populations could
potentially have, both in terms of the likelihood of
tendinopathy development and the extent of morbidity
experienced in the event that the condition does arise.
If a more aggressive, pharmacological approach
were warranted, Matarese et al14 highlighted the potential
for the use of agents such as metformin and thiazolidine,
which have anti-inflammatory actions. Both of these
agents are already commonly used in the management of
insulin resistance in patients with obesity and T2 diabetes,
thus making them especially good options with regard to
the prevention of complications linked to a systemic state
of low-grade inflammation.13
Careful consideration must be applied with regard to
the use of these agents in this context, as not all agents with
systemic anti-inflammatory actions may be suitable to
prevent site-specific pathology. For example, statins may be
a good choice of agent in the management of obese
individuals/T2 diabetics14 given their anti-inflammatory
properties. In addition, an increased ratio of low-density
lipoprotein to high-density lipoprotein cholesterol levels is a
notable risk factor for cardiovascular disease develop-
ment,34 and a possible risk factor for the development of
rotator cuff tendinopathy.35 Statins (3-hydroxy-3-methyl-
glutaryl coenzyme A reductase inhibitors) are efficacious in
lowering low-density lipoprotein-cholesterol concentration,
and are therefore commonly used for the prevention of
cardiovascular disease events.36 It would not be unreason-
able therefore to hypothesize that they may also offer a
potential role in the prevention of chronic tendinopathy.
However, the use of statins could actually predispose to the
development of tendinopathy.37 Although reports linking
tendinopathy with statin use are rare, caution should be
applied when considering their commencement in “high-
risk” individuals including those with metabolic disorders
such as T1/T2 diabetes.37
Battery and Maffulli Sports Med Arthrosc Rev � Volume 19, Number 3, September 2011
216 | www.sportsmedarthro.com r 2011 Lippincott Williams & Wilkins
A “one size fits all” approach cannot be employed
with regard to treating the systemic low-grade inflamma-
tory state, and care must be taken to consider the
demographics of each individualwhen commencing any
associated pharmacological treatment.
CONCLUSIONS
A prolonged state of systemic, low-grade inflamma-
tion, such as in obesity and states of impaired insulin
sensitivity, may act as a risk factor for a “failed healing
response” after an acute tendon insult, thus predisposing
affected individuals to the development of chronic over-
use tendinopathies. In association, simple measures, such
as lifestyle alterations and disease-specific interventions,
could make real difference with regard to both the
prevention and treatment of tendinopathy. However,
the potential also exists for a “double benefit” pharma-
cological approach, through the use of agents already
used in the treatment of obesity and diabetes, but also
known to have anti-inflammatory effects.
REFERENCES
1. Abate M, Gravare Silbernagel K, Siljeholm C, et al. Pathogenesis of
tendinopathies: inflammation or degeneration? Arthritis Res Ther.
2009;11:235.
2. Cook J, Purdam C. Is tendon pathology a continuum? A pathology
model to explain the clinical presentation of load-induced tendino-
pathy. Br J Sports Med. 2009;43:409.
3. Rees JD, Maffulli N, Cook J. Management of tendinopathy. Am J
Sports Med. 2009;37:1855–1867.
4. Maffulli N, Longo UG, Loppini M, et al. Current treatment options
for tendinopathy. Expert Opin Pharmacother. 2010;11:2177–2186.
5. Longo UG, Ronga M, Maffulli N. Achilles tendinopathy. Sports
Med Arthrosc. 2009;17:112–126.
6. Maffulli N, Longo UG, Maffulli GD, et al. Marked pathological
changes proximal and distal to the site of rupture in acute Achilles
tendon ruptures. Knee Surg Sports Traumatol Arthrosc. 2010. Epub
ahead of print: DOI: 10.1007/s00167-010-1193-2.
7. Maffulli N, Longo UG, Denaro V. Novel approaches for the manage-
ment of tendinopathy. J Bone Joint Surg Am. 2010;92:2604–2613.
8. Almekinders LC, Temple JD. Etiology, diagnosis, and treatment of
tendonitis: an analysis of the literature. Med Sci Sports Exerc.
1998;30:1183–1190.
9. Abate M. Pathogenesis of tendinopathies: inflammation or degen-
eration? Arthritis Res Ther. 2009;11:235.
10. Ramchurn N, Mashamba C, Leitch E, et al. Upper limb
musculoskeletal abnormalities and poor metabolic control in
diabetes. Eur J Intern Med. 2009;20:4.
11. Hirai S, Takahashi N, Goto T, et al. Functional food targeting the
regulation of obesity-induced inflammatory responses and pathol-
ogies. Mediators Inflamm. 2010;2010:367838.
12. Gaida J, Ashe M, Bass S, et al. Is adiposity an under-recognized risk
factor for tendinopathy? A systematic review. Arthritis Rheum. 2009;
61:840.
13. Roth CL, Kratz M, Ralston MM, et al. Changes in adipose-derived
inflammatory cytokines and chemokines after successful lifestyle
intervention in obese children. Metabolism. 2010.
14. Matarese G, Procaccini C, De Rosa V, et al. Regulatory T cells in
obesity: the leptin connection. Trends Mol Med. 2010;6:247–256.
15. Wendelboe AM, Hegmann KT, Gren LH, et al. Associations
between body-mass index and surgery for rotator cuff tendinitis.
J Bone Joint Surg Am. 2004;86-A:743.
16. Wenner M. Inflammatory clues. Scientific American. 2009;301:24–26.
17. Freeman JS. A physiologic and pharmacological basis for imple-
mentation of incretin hormones in the treatment of type 2 diabetes
mellitus. Mayo Clin Proc. 2010;85(12 suppl):S5–S14.
18. Lewis JS, Sandford FM. Rotator cuff tendinopathy: is there a role
for polyunsaturated Fatty acids and antioxidants? J Hand Ther.
2010;22:49.
19. Karousou E, Ronga M, Vigetti D, et al. Molecular interactions in
extracellular matrix of tendon. Front Biosci (Elite Ed). 2010;2:1–12.
20. Millar NL, Hueber AJ, Reilly JH, et al. Inflammation is present in
early human tendinopathy. Am J Sports Med. 2010;38:2085–2091.
21. Mavrikakis M, Drimis S, Kontoyannis DA, et al. Calcific shoulder
periarthritis (tendinitis) in adult onset diabetes mellitus: a controlled
study. Ann Rheum Dis. 1989;48:211.
22. Scott A, Lian Ø, Bahr R, et al. Increased mast cell numbers in
human patellar tendinosis: correlation with symptom duration and
vascular hyperplasia. Br J Sports Med. 2008;42:753.
23. Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med.
2009;360:1989–2003.
24. Avvedimento EV, Gabrielli A. Stiff and tight skin: a rear window
into fibrosis without inflammation. Sci Transl Med. 2010;2:13.
25. Raatikainen T, Karpakka J, Puranen J, et al. Operative treatment of
partial rupture of the patellar ligament-a study of 138 cases. Int J
Sports Med. 1994;15:46–49.
26. Potter H, Hannafin J, Morwessel R, et al. Lateral epicondylitis-
correlation of MR-imaging, surgical, and histopathologic findings.
Radiology. 1995;196:43–46.
27. Sullo A, Maffulli N, Capasso G, et al. The effects of prolonged
peritendinous administration of PGE1 to the rat Achilles tendon: a
possible animal model of chronic Achilles tendinopathy. J Orthop
Sci. 2001;6:349.
28. Cilli F, Khan M, Fu F, et al. Prostaglandin EB2 affects
proliferation and collagen synthesis by human patellar tendon
fibroblasts. Clin J Sports Med. 2004;14:232–236.
29. Khan K, Maffulli N. Tendinopathy: an achilles’ heel for athletes and
clinicians. Clin J Sports Med. 1998;8:151–154.
30. Thampatty BP, Im H-J, Wang JH. Leukotriene B4 at low dosage
negates the catabolic effect of prostaglandin E2 in human patellar
tendon fibroblasts. Gene. 2006;372:103.
31. Fu SC, Wang W, Pau HM, et al. Increased expression of
transforming growth factor-beta1 in patellar tendinosis. Clin Orthop
Relat Res. 2002;4:174.
32. Rada´k Z, Takahashi R, Kumiyama A, et al. Effect of aging and late
onset dietary restriction on antioxidant enzymes and proteasome
activities, and protein carbonylation of rat skeletal muscle and
tendon. Exp Gerontol. 2002;37:1423.
33. Longo UG, Franceschi F, Ruzzini L, et al. Higher fasting plasma
glucose levels within the normoglycaemic range and rotator cuff
tears. Br J Sports Med. 2009;43:284–287.
34. Gotto AM Jr. Triglyceride as a risk factor for coronary artery
disease. Am J Cardiol. 1998;82:22Q–25Q.
35. Longo UG, Franceschi F, Spiezia F, et al. Triglycerides and total
serum cholesterol in rotator cuff tears: do they matter? Br J Sports
Med. 2010;44:948–951.
36. NICE) NIfHaCE. Statins for the prevention of cardiovascular
events: National Institute for Health and Clinical Excellence (NICE)
2008 Contract No.: T094.
37. Marie I, Delafeneˆtre H, Massy N, et al. Tendinous disorders
attributed to statins: a study on ninety-six spontaneous reports in
the period 1990-2005 and review of the literature. Arthritis Rheum.
2008;59:367.
Sports Med Arthrosc Rev � Volume 19, Number 3, September 2011 Inflammation in Overuse Tendon Injuries
r 2011 Lippincott Williams & Wilkins www.sportsmedarthro.com | 217