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Review doi:10.1093/rheumatology/kes395
Occurrence of tendon pathologies in metabolic
disorders
Michele Abate
1
, Cosima Schiavone
1
, Vincenzo Salini
1
and Isabel Andia
2
Abstract
This article reviews the pathogenetic role of metabolic disorders, which are of paramount relevance to the
progression of tendon damage. In diabetes, the prevalence of rheumatological diseases is high, mainly
because of the deleterious effects of advanced glycation end products that deteriorate the biological and
mechanical functions of tendons and ligaments. In heterozygous familial hypercholesterolaemia, most
patients develop Achilles xanthomatosis, a marker of high risk for cardiovascular disease caused by
cholesterol deposition in the tendons. Tendon degeneration has also been observed in non-familial hyper-
cholesterolaemia. Monosodium urate crystal depositions in soft tissues are hallmarks of chronic gouty
arthritis. In this group of diseases, the mobilization of cholesterol and uric acid crystals is presumably
followed by low-grade inflammation, which is responsible for tendon degeneration. Adiposity may con-
tribute to tendon disorders via two different mechanisms: increased weight on the load-bearing tendons
and systemic dysmetabolic factors that trigger subclinical persistent inflammation. Finally, tendon abnorm-
alities have been observed in some rare congenital metabolism disorders such as alkaptonuria.
Key words: tendinopathy, diabetes mellitus, hypercholesterolaemia, hyperuricaemia, obesity.
Introduction
Progress in research has increased our understanding of
tendon physiology and the pathogenetic pathways of
chronic tendinopathies. Trans-membrane proteins called
integrins connect the extracellular collagen fibrils to the
cytoskeleton of tenocytes. Under normal exercise condi-
tions, fibril stretching activates subcellular biology,
releasing growth factors and triggering the subsequent
synthesis of extracellular matrix components, pre-
dominantly proteoglycans and collagen neofibrils [1].
Homeostasis is maintained by the simultaneous produc-
tion of appropriate metalloproteinases (MMPs), which
counteracts the anabolic effects of growth factors [2].
When fibril stretching is increased but remains within the
physiological window, synthesis prevails over degradation
and tendon hypertrophy occurs. However, when repeated
loading deviates from normal limits by differences in
magnitude, frequency, duration and/or direction, overuse
injury may develop. An aberration in proteoglycan me-
tabolism is likely to drive the pathogenesis of tendon dam-
age, as excess proteoglycan production leads to water
retention and pressure from swelling. The biochemical
adaptation to these changes involves the production of
pro-inflammatory agents such as IL-1 b, TNF-a and pros-
taglandins (PG). Some of the detrimental effects of these
pro-inflammatory cytokines include enhanced production
of MMPs that cause matrix destruction.
The following pathogenetic cascade is very complex
and involves tenocyte apoptosis, hypoxia, neovessel
proliferation, smoldering disorganized fibrillogenesis, col-
lagen fibre disruption and hyaline and mucoid degener-
ation, usually with an absence of inflammation in the
advanced stages [14].
Of note, the progression of the disease is characterized
by substantial individual differences. Indeed, tendon in-
tegrity is disrupted at comparably high loads only in
some individuals, and in a small subset of individuals,
exposed to such environmental chemicals as fluoroquino-
lone antibiotics and statins, tendon integrity disruption
can occur even within a normal mechanical load range
[5]. Intrinsic and extrinsic factors, including genetics,
age, drugs, hormones and blood supply, influence the
biological milieu and tendon adaptation to mechanical
loading.
1
Department of Medicine and Science of Aging, University G.
d’Annunzio, Chieti-Pescara, Italy and
2
BioCruces Health Research
Institute, Cruces University Hospital, Barakaldo, Spain
Correspondence to: Michele Abate, Department of Medicine and
Science of Aging, University G. d’Annunzio, Chieti-Pescara, Via dei
Vestini 31, 66013 Chieti Scalo [CH], Italy.
E-mail: m.abate@unich.it
Submitted 20 June 2012; revised version accepted
23 November 2012.
!
The Author 2013. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com
1
RHEUMATOLOGY 270
REVIEW
Rheumatology Advance Access published January 12, 2013
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In this context, the role of metabolic factors is of para-
mount importance. Clinical and experimental research
shows that diabetes [6], obesity [7] and, to a lesser
extent, hypercholesterolaemia [8], hyperuricaemia [9]
and some rare congenital metabolism disorders (alkapto-
nuria, glucose-6-phosphatase deficiency and hypergalac-
tosaemia) [10] are frequently associated with tendon
degeneration, thus influencing the mechanical properties
of tendons and even impairing the healing process after
surgery. The aim of this review is to summarize the pre-
sent knowledge on this topic and to analyse the mechan-
isms for the negative effects of these metabolic disorders.
A search of English language articles was performed in
PubMed, Web of Knowledge (WOK) and EMBASE using
the key search terms tendinopathy or tendon, combined
with obesity, diabetes, hypercholesterolaemia, hyperuri-
caemia, alkaptonuria, glucose-6-phosphatase or hyper-
galactosaemia, independently. Bibliographies were hand
searched to include any applicable studies that were not
captured by our search. Articles were eligible if they pro-
vided specific information related to the correlation be-
tween tendon disease and metabolic disorders.
Diabetes
Clinical observations
Several rheumatological conditions complicate the clinical
course of diabetes mellitus. For example, Dupuytren’s
disease, characterized by thickening, shortening and
fibrosis of the palmar fascia, and trigger finger (also
called flexor tenosynovitis) have been found in 1015%
of subjects with diabetes versus 1% in non-diabetic con-
trols (matched for age and sex). Similarly, carpal tunnel
syndrome and shoulder adhesive capsulitis (frozen shoul-
der) have been reported in 1125% and 1020% of pa-
tients with diabetes, respectively. The prevalence of these
conditions increases with the duration of both Type I and
Type II diabetes and with poor glycaemic control [1113].
Symptomatic rotator cuff tears (Fig. 1) are more com-
monly observed both in subjects with overt Type I or
Type II diabetes [14, 15] and in those with high, yet
normal, plasma glucose levels [16]. In asymptomatic dia-
betic subjects, an increased thickness of supraspinatus
and biceps tendons and a significantly higher prevalence
of tears have been found [17]. These observations are of
clinical relevance because, as follow-up studies show
[18], pain and functional limitation are likely to occur in a
large percentage of people with asymptomatic tears at
baseline. In addition, after surgical repair, subjects with
diabetes show a restricted range of shoulder motion [19]
and a higher incidence of retears [20]. These adverse out-
comes can be related to the intrinsically poor quality of the
tissue that is being repaired.
In the lower limbs, increased thickness and structural
abnormalities of the plantar fascia and Achilles tendon
have been observed in both Type I and Type II diabetes
mellitus using sonography or magnetic resonance imaging
[2124]. These changes are more severe in patients with
neuropathic complications and previous foot ulcers but
can also be found in subjects without diabetic complica-
tions [25, 26].
Accordingly, reduced ankle joint range of motion, which
may restrain the forward progression of the tibia on the
fixed foot during the stance phase of walking, has been
documented in patients with diabetes [27, 28]. This in turn
results in prolonged and excessive weight-bearing stress
under the metatarsal heads during the footfloor inter-
action, which is thought to contribute to the development
of foot ulcers in individuals with diabetes mellitus [2830].
Imaging techniques, such as magnetic resonance imaging
and the more widely used sonography, show that
disorganized echotexture, focal hypoechoic areas and
increased thickness of the tendons and ligaments are
common in diabetic patients [2124].
Histopathology
According to clinical observations, histopathology shows
that joint capsules, ligaments and tendons lose their
normal glistening white appearance. In the more affected
portions, these structures become grey and amorphous,
with poorly marked areas where diffuse, fusiform or nodu-
lar thickening may be observed. Electron microscopic in-
vestigation shows that collagen fibrils appear twisted,
curved, overlapping and otherwise highly disorganised.
There is an increased packing density of collagen fibrils,
with a decreased number of fibroblasts and tenocytes per
unit of surface area. The reduction of elastic fibres is con-
sistent. Finally, the number of capillaries per unit of sur-
face area, and therefore the arterial blood flow, is
reduced, particularly in elderly subjects [31].
Pathogenesis
According to an accepted hypothesis, tendon damage in
diabetes is caused by an excess of advanced glycation
end products (AGEs; Fig. 2). AGEs form at a constant but
slow rate and accumulate with time in the normal body.
However, their formation is markedly accelerated in dia-
betes because of the increased availability of glucose.
F
IG.1Complete supraspinatus tear in a 61-year-old
diabetic patient.
A small, full defect (insertional portion) in the tendon from
the bursal to the articular margin, with retracted tendon
end (calipers), is observed (A, transverse scan). In the
same patient, an effusion (anechoic area, arrows) in the
bicipital tendon sheath can also be detected (B, trans-
verse scan). B: bicipital tendon; SST: supraspinatus
tendon; D: deltoid muscle; H: humeral bone.
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A key characteristic of reactive AGEs is their ability to form
a covalent cross-link within collagen fibres, altering their
structure and functionality [13].
Essentially, collagen cross-links can generate via
two different pathways: (i) the enzymatically driven,
hydroxylysine-derived aldehyde pathway and (ii) the
non-enzymatic glycation or oxidation-induced AGE
cross-link [3234]. As opposed to the beneficial effects
on collagen strength bestowed by enzymatic cross-links,
AGE cross-linking is generally thought to cause deteriora-
tion of the biological and mechanical function of tendons
and ligaments [35]. In fact, once formed, AGEs can be
degraded only when the protein they are linked to is
itself degraded. Therefore the most extensive accumula-
tion of AGEs will occur in tissues with low turnover, such
as cartilage, bone and tendon.
Other major features of AGEs relate to their interactions
with a variety of cell-surface AGE-binding receptors (i.e.
AGE-R1, AGE-R2, AGE-R3 and RAGE) [36]. Ligand en-
gagement of AGE-binding receptors activates several crit-
ical molecular pathways and triggers a number of effects,
including pro-oxidant events, via generation of reactive
oxygen species, and further pro-inflammatory events via
NF-ib signalling [37]. This in turn accelerates AGE
cross-linking in collagen fibres and leads to sustained
upregulation of pro-inflammatory mediators and to a dys-
functional cell phenotype [38, 39].
Further AGE negative effects include (i) the modification
of short-lived proteins, such as the basic fibroblast growth
factors, which is followed by markedly decreased mito-
genic activity; (ii) intracellular AGE formation, which leads
to the quenching of nitric oxide and impaired growth
factor signalling and (iii) enhanced apoptosis via oxidative
stress, increased caspase activities and/or extrinsic sig-
nalling through pro-apoptotic cytokines [40, 41].
Tendon damage ensues from these complex pathways.
In addition to degeneration, tendon and ligament thick-
ness increases as expression of the abnormal storage
and the architectural distortion of collagen layers [42,
43]. From the biomechanical point of view, several studies
have demonstrated that collagen toughness and stiffness
and the elastic modulus are strongly influenced by AGE
cross-link formation [44, 45].
In addition to the AGE-mediated pathogenetic mechan-
ism, hyperglycaemia in itself may lead to alterations in the
redox environment, specifically in the polyol pathway, re-
sulting in increased intracellular water and cellular
oedema. Microvascular disease may lead to tissue
F
IG.2Common pathogenetic pathways of tendon damage in metabolic disoders.
Diabetes and obesity are the best-known factors of tendon degeneration. Hypecholesterolaemia and hyperuricaemia are
frequently associated. The ensuing collagen cross-linking, tenocyte apoptosis and release of inflammatory cytokines lead
progressively to tendon damage.
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hypoxia with overproduction of oxygen free radicals,
creating a permissive apoptotic environment [46].
It is not surprising that these metabolic abnormalities
may be present in the early clinical stages of Type II dia-
betes [24]. Indeed, while Type I diabetes is diagnosed at
an early stage because of a relatively acute clinical onset
characterized by extreme elevations in glucose concen-
trations, Type II diabetes is usually diagnosed later, when
many patients already exhibit chronic complications.
Certainly these subjects could have glucose intolerance
or mild Type II diabetes mellitus for a significant length of
time before diabetes is clinically diagnosed.
The ultrasonographic finding of reduced neovas-
cularization inside the degenerated tendons [47] is con-
sistent with several observations that show decreased
vascular endothelial growth factor levels and reduced
angiogenesis in different experimental and clinical dia-
betic conditions [4850]. This finding adds to our know-
ledge about the pathogenesis of diabetic tendinopathy.
The downregulation of this factor can limit vessel and
nerve ingrowth and can also affect neurogenesis, redu-
cing neural progenitor cell recruitment, axonal outgrowth,
neuronal survival and the proliferation of Schwann cells
[51]. The association between reduced nerve proliferation
inside tendons and sensitive neuropathy reduces pain
perception. Consequently, diabetic patients, who lack dis-
tress signals, may excessively exercise their tendons,
making them prone to overuse damage.
Hypercholesterolaemia
Clinical observations and histopathology
Heterozygous familial hypercholesterolaemia (HeFH) is
caused by a defect in the catabolism of low-density lipo-
protein (LDL), usually resulting from the inheritance of a
mutant LDL receptor gene. Untreated HeFH is associated
with a high mortality and morbidity from coronary heart
disease, but when intensive treatment occurs early, life
expectancy can be substantially improved.
Most patients with HeFH develop tendon xanthoma,
mainly in the Achilles tendon (Fig. 3), which becomes in-
creasingly common from the third decade onwards. The
early detection of xanthoma is thus exceptionally import-
ant. Unfortunately, in several cases the clinical diagnosis
is difficult because the nodules are too small to be de-
tected or because the pain is ascribed to an unspecific
tenosynovitis. In this regard, Beeharry et al. [52] have
shown that episodes of Achilles tendon pain lasting
more than 3 days are very common in patients with
HeFH, even in the absence of apparent xanthomatosis.
Therefore these authors suggest that serum cholesterol
measurement in young patients presenting with a painful
Achilles tendon is mandatory because it could allow the
early diagnosis of HeFH.
Sonography is very useful for detecting tendon abnorm-
alities (Grade 1: minor sonographic changes; Grade 2:
diffuse heterogeneous echo pattern; Grade 3: focal
hypoechoic lesions). Sonography can visualize xanthoma
located deep within the tendon that cannot be detected
by palpation. Tsouli et al. [53], in a large casecontrol
study, found a Grade 2 Achilles tendon echostructure in
30 of 80 patients and a Grade 3 in 8 of 80 patients. The
thickness of the tendon was increased in patients with
HeFH compared with controls in proportion to the echo-
structural abnormalities. Only patients with minor sono-
graphic changes showed significant reductions in
Achilles tendon thickness after statin treatment (from
4.9 ± 0.55 mm to 4.5 ± 0.43 mm, P < 0.01), whereas pa-
tients with Grade 2 and Grade 3 abnormal echostructures
remained unchanged, and no significant reduction was
observed [53]. Exacerbations of Achilles tendinopathy
can occur when statin treatment is started and is attribut-
able to the rapid lowering of cholesterol [53]. The condi-
tion would seem to be akin to the exacerbations of gout
that occur when allopurinol treatment begins and the
serum uric acid level decreases rapidly. The mobilization
of cholesterol, like that of uric acid crystals, presumably
provokes an inflammatory cell reaction [52, 54].
Histologically, cholesterol deposition is observed both
extracellularly and inside histiocytes and other foam cells,
which show numerous intracytoplasmic lipid vacuoles,
lysosomes and myelin figures. An inflammatory cell infil-
trate and a fibrous reaction may be associated.
The deleterious effects of non-familial hypercholesterol-
aemia on tendons have been debated. Some studies have
shown that in patients with Achilles tendon rupture, the
concentration of serum lipids is higher than in controls [8]
and that the esterified fraction of cholesterol is elevated
in biopsies from degenerated Achilles tendons [55].
However, in a study comparing the sonographic charac-
teristics of Achilles tendon in subjects with familial hyper-
cholesterolaemia with those of patients with non-familial
hypercholesterolaemia, abnormal patterns were noted
only in subjects with familial hypercholesterolaemia [56].
Similarly, conflicting results have been reported for rotator
cuff tendons. According to Abboud et al. [57], total chol-
esterol, triglycerides and LDL cholesterol concentrations
F
IG.3Bilateral Achilles tendon abnormalities in a
53-year-old hypercholesterolaemic patient.
Both midportion Achilles tendons appear hypoechoic,
dishomogeneous and thickened (calipers), with loss of the
normal fibrillar pattern (longitudinal scan). Neovessels
inside the tendon can be detected by means of power
Doppler examination (panel 1). Panel 1: left Achilles
tendon; Panel 2: right Achilles tendon.
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are higher in patients with rotator cuff tendon tears, and
their high-density lipoprotein cholesterol is lower than that
of the control group. However, these results are chal-
lenged by the findings of Longo et al. [58] who found no
differences in the lipid profiles of subjects who underwent
surgery for rotator cuff tears or meniscectomy.
Pathogenesis
The pathogenetic mechanisms leading to the formation of
xanthoma have been elucidated. LDL derived from the
circulation accumulate into tendons and become oxi-
dized. Oxidized LDL (oxLDL) contains various oxidatively
modified phospholipids and cholesterols, isoprostanes,
oxidized arachidonoyl residues, lysolipids and lysopho-
sphatidic acid [59]. As might be expected from this, the
effect of oxLDL on inflammatory cells is complex, depend-
ent on the concentration of the particles and the extent
and mode of oxidation [60]. It is worth mentioning that
specific oxidative-truncated phospholipids rapidly enter
nucleated cells, travel to the mitochondria and initiate
the mitochondrial dependent pathway to apoptotic cell
death [59].
Artieda et al. [61] have shown that macrophages from
HeFH patients with tendon xanthoma have a higher pre-
disposition to form foam cells after oxLDL overload than
those from HeFH patients without xanthoma. Moreover,
macrophages from HeFH patients exhibit a differential
gene expression profile characterized by increased
plasma tryptase, TNF-a, IL-8 and IL-6 expression [61].
In a familial form of massive tendon xanthomatosis,
Matsuura et al. [62] showed decreased high-density
lipoprotein-mediated cholesterol efflux associated with
genetic variation in the reverse cholesterol transport and
LDL oxidation pathways [63]. Interestingly, xanthomatosis
and atherosclerosis share these genetic abnormalities and
therefore may result from the same pathophysiological
mechanisms. This explains why tendon xanthoma is a
marker of high risk for cardiovascular disease.
The mechanism by which non-familial hypercholester-
olaemia subjects develop damaged tendon tissues is
unknown. It has been hypothesized that microscopic
cholesterol deposition inside the tendons, undetectable
with the usual imaging techniques, could initiate and
maintain a low-grade, persistent inflammation; this, in
turn, may be responsible for chronic tendon degeneration
and biomechanical changes, as shown by experimental
studies of the patellar and rotator cuff tendons of hyperch-
olesterolaemic knockout mice [64].
Hyperuricaemia
Clinical observations and histopathology
Monosodium urate monohydrate (MSU) crystal depos-
itions (called tophi from the Latin word tofus, porous
stone) in joints (cartilage, synovial membranes and ten-
dons) and in other soft tissues are hallmarks of chronic
gouty arthritis. In inter-critical periods, they appear as in-
dolent nodules, which are difficult to differentiate from
rheumatoid nodules and other types of subcutaneous
nodules. Gout is diagnosed with certainty upon the finding
of MSU crystals. Evaluated via polarized light microscopy,
these crystals are typically needle-shaped and negatively
birefringent, whereas calcium pyrophosphate dehydrate
crystals (pseudogout) are weakly positively birefringent
and more rectangular than MSU crystals. Specific diag-
nostic sonographic features include a hyperechoic, irregu-
lar band over the superficial margin of the articular
cartilage described as a double contour sign; hypoechoic
to hyperechoic, inhomogeneous material surrounded by a
small anechoic rim represents tophaceous material [65].
An increase of blood flow surrounding MSU deposits
using power Doppler has been described as an indicator
of inflammatory activity [66]. The histopathological equiva-
lent of the anechoic rim is the tophus wall, formed by
macrophages, lymphocytes and large foreign body giant
cells.
Gouty arthritis is predominantly a disease of the lower
extremities. The toe is the most common site of initial in-
volvement, followed in order of frequency by the ankles,
heel, knee, wrists, fingers and elbows. Gouty bursitis also
occurs, and the pre-patellar and olecranon bursae are the
most commonly involved sites.
Interestingly, urate deposits in tendons and the syno-
vium and the prevalence of patellar and Achilles entheso-
pathy (15% vs 1.9%; P = 0.0007) occur more frequently in
subjects with asymptomatic hyperuricaemia than in
asymptomatic, normouricaemic individuals [9, 67].
Pathogenesis
The mechanisms of MSU deposition have been eluci-
dated. In vitro studies show that when serum uric acid
levels reach approximately 7 mg/dl, MSU crystals begin
to precipitate. However, the in vivo threshold of precipita-
tion depends on several biological factors. Traumas,
mechanical stress and lower temperature favour MSU
precipitation and explain the frequent localization of
tophi in the first metatarsalphalangeal joint and the
helix of the ear. Poor blood supply also plays a role, as
shown by the preferential deposition in tissue with little or
absent vascularization (tendon, ligaments and cartilage).
Other factors that can contribute to the decreased solu-
bility of sodium urate and crystallization are alterations in
the extracellular matrix, which lead to an increase in non-
aggregated proteoglycans, chondroitin sulfate, insoluble
collagen fibrils and other molecules in the affected
joint [54].
Chronic cumulative urate crystal deposition leads to
tophi formation. Tophi are usually walled off, but
microtrauma-related changes in the size and packing of
the crystal may loosen tophi from the organic matrix. This
activity leads to crystal shedding and facilitates crystal
interaction with residential inflammatory cells, leading to
an acute gouty flare. A variety of inflammatory mediators,
such as IL-1b, chemokines and PGs, are released. A
number of factors have been identified to explain the
self-resolution of the acute attack: crystal dissolution
or coating with proteins, neutrophil apoptosis, the
inactivation of inflammatory mediators and the release of
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anti-inflammatory mediators. As for cholesterol, it
is highly probable that microscopic deposition of MSU
crystals can occur in tendons, followed by low-grade
persistent inflammation that causes chronic tendon de-
generation [67].
Obesity
Clinical observations
Adiposity is a well-known risk factor for tendinopathies [7].
Load-bearing tendons, such as the Achilles and patellar
tendons, are more frequently affected, and plantar fasciitis
is commonly observed [28, 6870]. Recently adiposity
has also been recognized as a risk factor for tendinopathy
in non-load-bearing tendons. A positive correlation has
been found between increasing adiposity and rotator
cuff tendinopathy [71], and obesity has also been shown
to have a negative impact on the functional outcomes
after arthroscopic rotator cuff repair surgery [72].
Further studies have shown that the probability of
tendon abnormalities is higher in males with an increased
waist circumference (74% in subjects with a waist
circumference >83 cm vs 15% in males with a waist
circumference <83 cm). In a population-based study,
asymptomatic Achilles tendon pathology was associated
with central fat distribution in men and peripheral fat dis-
tribution in women. It has been hypothesized that in men
Achilles tendon pathology is linked to metabolic syn-
drome, whereas in women oestrogens may prevent the
central accumulation of adipose tissue [73]. In another
study, Gaida et al. [74] observed that subjects with symp-
tomatic Achilles tendinopathy had higher triglyceride
levels (P = 0.039), lower HDL cholesterol (HDL-C)
(P = 0.016), higher triglyceride/HDL-C ratio (P = 0.036)
and further elevated apolipoprotein B concentration
(P = 0.017) compared with controls matched for gender,
age and body mass index. Typically this pattern of dysli-
pidaemia is displayed by individuals with insulin resist-
ance and is common in those with metabolic syndrome.
Pathogenesis
Prevailing hypotheses of tendon damage in obese sub-
jects are associated with two different mechanisms: the
increased yield on the load-bearing tendons and the
biochemical alterations attributed to systemic dysmeta-
bolic factors.
Indeed, weight-bearing tendons are exposed to higher
loads with increasing adiposity, and the higher loads lead
to overuse tendinopathy. Alternatively, the systemic hy-
pothesis is based on studies showing that the association
with adiposity is equally strong for the non-load-bearing
and load-bearing tendons [74].
Adipose tissue is now recognized as a major endocrine
and signalling organ. In obese subjects, adipose tissue
releases bioactive peptides and hormones; the adipoki-
nome includes a full range of proteins such as chemerin,
lipocalin 2, serum amyloid A3, leptin and adiponectin [75].
These proteins influence several activities in various mes-
enchymal cell phenotypes (tenocytes, chondrocytes and
osteocytes), which may directly modify tendon structure.
In particular, adipokines are able to modulate cytokines,
prostanoids and MMP production [76, 77].
The persistently raised serum levels of PGE2, TNF-a
and LTB4 observed in obesity and in subjects with
impaired insulin sensitivity provide supplementary evi-
dence that a systemic state of chronic, subclinic,
low-grade inflammation is present in these conditions
and may act as a prolonged disruptor of tendon homeo-
stasis [7881].
Moreover, the migration of immune cells, such as
macrophages and mast cells, into adipose tissue is asso-
ciated with a decrease in the circulating levels of these
cells. As a consequence, the release of pro-fibrotic fac-
tors, such as TGF-b, is reduced, and this may have a
detrimental effect on tendon healing, especially if the pro-
duction of Type I and III collagen is also reduced [81, 82].
In subjects with visceral fat, the cluster of metabolic
abnormalities is considered the consequence of insulin
resistance [73]. Elevated insulin concentrations fail to
stimulate increased glucose uptake into muscle, which
leads to fasting hyperglycaemia, impaired glucose toler-
ance and eventually Type II diabetes mellitus. Therefore
AGE formation is increased in obesity.
So, it is evident that obesity and diabetes share
common pathogenetic pathways characterized by
increased cross-linking between collagen fibrils mediated
by AGEs and low-grade inflammation, both of which amp-
lify the deleterious effect of tendon overuse (Fig. 2)[73].
Interestingly, ultrastructural studies demonstrate that
genetically obese Zucker rats have a relative prevalence
of larger collagen fibrils as a consequence of excessive
covalent cross-links. Consequently, the fibril diameter
shows unimodal distribution, in contrast with the bimodal
pattern observed in regularly exercised lean animals.
Because thin fibrils confer greater elasticity to tendons,
the relative lack of these fibrils in obese animals could
be responsible for increased stiffness and microruptures
as a consequence of excessive exercise [83].
Congenital metabolism disorders
Tendon abnormalities have also been described in some
inherited metabolism disorders.
Alkaptonuria is a rare inborn metabolic disease caused
by a deficiency of the enzyme homogentisic acid oxidase,
which is involved in the metabolism of homogentisic acid,
a metabolic product of the aromatic amino acids phenyl-
alanine and tyrosine. The homogentisic acid accumulates
in the fibrillary collagens and binds to them irreversibly,
becoming polymerized to form a dark pigment, which
confers a characteristic ochre or yellow appearance to
connective tissues (ohcronosis). The accumulation of
homogentisic acid inhibits collagen cross-linking, leading
to a reduction in the structural integrity of collagen, thus
increasing the likelihood of spontaneous rupture [84].
By the fourth or fifth decade, the disease usually pro-
gresses from simple alkaptonuria (characterized by dark
urine caused by homogentisic acid and without symp-
toms) to alkaptonuric arthropathy in approximately 30%
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of subjects [10]. Achilles and patellar tendons are more
frequently affected; they appear yellow or brown, defibril-
lated and degenerated, mainly at the site of the tendon’s
insertion into bone (enthesis). Ruptures, frequently spon-
taneous, occur in about 2030% of cases [85, 86].
Hyperuricaemia is a well-known consequence of
glucose-6-phosphatase deficiency, the enzymatic abnor-
mality that characterizes glycogen storage disease. Gouty
tenosynovitis is a very rarely occurring manifestation of
this congenital disease [87].
Finally, for the sake of thoroughness, it must be noted
that increased tendon collagen cross-linking by non-
enzymatic galactosylation has been observed in cases
of congenital hypergalactosaemia. However, to our know-
ledge, no clinical tendinopathies have been described in
this disease [88].
Conclusions
Ample evidence shows that metabolic disorders have
deleterious effects on tendons and favour tendon degen-
eration. This observation has relevant clinical implications.
Subjects with diabetes or who are overweight, particularly
young people practicing sport activities, should maintain
adequate dietary regimens and pharmacological treat-
ments to achieve a proper body weight and metabolic
control. Because physical exercise is an important thera-
peutic measure, the program of physical activity should
be individually prescribed; indeed, an excess of exercise
could favour tendon degeneration.
Subjects who participate in sports that selectively over-
load some tendons (e.g. running) should be monitored
more frequently. Orthopaedic surgeons must be aware
that when a dysmetabolic condition is present, the healing
of fractures is delayed, the osseointegration of autologous
bone grafts is sometimes unsatisfactory and post-surgery
complications are more frequent. Therefore the treatment
of diabetes, obesity, hypercholesterolaemia and hyperur-
icaemia before and after orthopaedic surgery is manda-
tory to minimize negative outcomes and to reduce the
length of hospital stay.
In subjects referred to orthopaedic observation for
tendinopathies or tendon tears, the possibility of undiag-
nosed hypercholesterolaemia, diabetes or glucose intoler-
ance should be considered. Finally, the treatment of
dysmetabolic risk factors could be an additional strat-
egy to slow the progression of asymptomatic
tendinopathies.
Rheumatology key messages
. Tendon degeneration is often caused by metabolic
disorders (e.g. diabetes, hypercholesterolaemia,
hyperuricaemia and obesity).
. Proper control of diabetes, obesity, hypercholes-
terolaemia and hyperuricaemia could minimize
negative effects on tendons.
. Hypercholesterolaemia, diabetes or glucose intoler-
ance should be considered when treating subjects
affected by tendinopathies.
Acknowledgements
All authors participated in the work and agreed to the
submission of the paper to the journal.
Disclosure statement: The authors have declared no
conflicts of interest.
References
1 Heinemeier KM, Kjaer M. In vivo investigation of tendon
responses to mechanical loading. J Musculoskelet
Neuronal Interact 2011;11:11523.
2 Parkinson J, Samiric T, Ilic MZ et al. Involvement of pro-
teoglycans in tendinopathy. J Musculoskelet Neuronal
Interact 2011;11:8693.
3 Abate M, Silbernagel KG, Siljeholm C et al. Pathogenesis
of tendinopathies: inflammation or degeneration? Arthritis
Res Ther 2009;11:235.
4 Thornton GM, Hart DA. The interface of mechanical
loading and biological variables as they pertain to the
development of tendinosis. J Musculoskelet Neuronal
Interact 2011;11:94105.
5 Dirks RC, Warden SJ. Models for the study of
tendinopathy. J Musculoskelet Neuronal Interact 2011;11:
1419.
6 Ramchurn N, Mashamba C, Leitch E et al. Upper limb
musculoskeletal abnormalities and poor metabolic control
in diabetes. Eur J Intern Med 2009;20:71821.
7 Gaida JE, Cook JL, Bass SL. Adiposity and tendinopathy.
Disabil Rehabil 2008;30:155562.
8 Ozgurtas T, Yildiz C, Serdar M et al. Is high concentration
of serum lipids a risk factor for Achilles tendon rupture?
Clin Chim Acta 2003;331:258.
9 Pineda C, Amezcua-Guerra LM, Solano C et al. Joint and
tendon subclinical involvement suggestive of gouty arth-
ritis in asymptomatic hyperuricemia: an ultrasound con-
trolled study. Arthritis Res Ther 2011;13:R4.
10 Perry MB, Suwannarat P, Furst GP et al. Musculoskeletal
findings and disability in alkaptonuria. J Rheumatol 2006;
33:22805.
11 Rosenbloom AL, Silverstein JH. Connective tissue and
joint disease in diabetes mellitus. Endocrinol Metab Clin
North Am 1996;25:47383.
12 Aydeniz A, Gursoy S, Guney E. Which musculoskeletal
complications are most frequently seen in type 2 diabetes
mellitus? J Int Med Res 2008;36:50511.
13 Abate M, Schiavone C, Pelotti P et al . Limited joint mobility
in diabetes and ageing: recent advances in pathogenesis
and therapy. Int J Immunopathol Pharmacol 2010;23:
9971003.
14 Viikari-Juntura E, Shiri R, Solovieva S et al. Risk factors
of atherosclerosis and shoulder pain—is there an
association? A systematic review. Eur J Pain 2008;12:
41226.
15 Cole A, Gill TK, Shanahan EM et al. Is diabetes associated
with shoulder pain or stiffness? Results from a population
based study. J Rheumatol 2009;36:3717.
www.rheumatology.oxfordjournals.org 7
Tendinopathy and metabolic disorders
by guest on January 14, 2013http://rheumatology.oxfordjournals.org/Downloaded from
16 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:
2847.
17 Abate M, Schiavone C, Salini V. Sonographic evaluation of
the shoulder in asymptomatic elderly subjects with dia-
betes. BMC Musculoskelet Disord 2010;11:278.
18 Yamaguchi K, Tetro AM, Blam O et al. Natural history of
asymptomatic rotator cuff tears: a longitudinal analysis of
asymptomatic tears detected sonographically. J Shoulder
Elbow Surg 2001;10:199203.
19 Namdari S, Green A. Range of motion limitation after ro-
tator cuff repair. J Shoulder Elbow Surg 2010;19:2906.
20 Clement ND, Hallett A, MacDonald D et al. Does diabetes
affect outcome after arthroscopic repair of the rotator
cuff? J Bone Joint Surg Br 2010;92:11127.
21 Duffin AC, Lam A, Kidd R et al. Ultrasonography of plantar
soft tissues thickness in young people with diabetes.
Diabet Med 2002;19:1009 13.
22 Batista F, Nery C, Pinzur M et al. Achilles tendinopathy in
diabetes mellitus. Foot Ankle Int 2008;29:498501.
23 Akturk M, Ozdemir A, Maral I et al. Evaluation of Achilles
tendon thickening in type 2 diabetes mellitus. Exp Clin
Endocrinol Diabetes 2007;115:926.
24 Abate M, Schiavone C, Di Carlo L et al. Achilles tendon and
plantar fascia in recently diagnosed type II diabetes: role of
body mass index. Clin Rheumatol 2012;31:110913.
25 Papanas N, Courcoutsakis N, Papatheodorou K et al.
Achilles tendon volume in type 2 diabetic patients with or
without peripheral neuropathy: MRI study. Exp Clin
Endocrinol Diabetes 2009;117:6458.
26 Lavery LA, Armstrong DG, Wunderlich RP et al. Predictive
value of foot pressure assessment as part of a
population-based diabetes disease management pro-
gram. Diabetes Care 2003;26:106973.
27 Andersen H, Mogensen PH. Disordered mobility of large
joints in association with neuropathy in patients with
long-standing insulin-dependent diabetes mellitus. Diabet
Med 1997;14:2217.
28 Pascual Huerta J, Garcı
´
a JM, Matamoros EC et al.
Relationship of body mass index, ankle dorsiflexion, and
foot pronation on plantar fascia thickness in healthy,
asymptomatic subjects. J Am Podiatr Med Assoc 2008;
98:37985.
29 Cronin NJ, Peltonen J, Ishikawa M et al. Achilles tendon
length changes during walking in long-term diabetes pa-
tients. Clin Biomech (Bristol, Avon) 2010;25:47682.
30 Giacomozzi C, D’Ambrogi E, Uccioli L et al. Does the
thickening of Achilles tendon and plantar fascia contribute
to the alteration of diabetic foot loading? Clin Biomech
(Bristol, Avon) 2005;20:5329.
31 Grant WP, Sullivan R, Sonenshine DE et al. Electron
microscopic investigation of the effects of diabetes melli-
tus on the Achilles tendon. J Foot Ankle Surg 1997;36:
2728.
32 Fujii K, Yamagishi T, Nagafuchi T et al. Biochemical
properties of collagen from ligaments and periarticular
tendons of the human knee. Knee Surg Sports Traumatol
Arthrosc 1994;2:22933.
33 Eyre DR, Paz MA, Gallop PM. Cross-linking in collagen
and elastin. Annu Rev Biochem 1984;53:71748.
34 Saito M, Marumo K. Collagen cross-links as a determinant
of bone quality: a possible explanation for bone fragility in
aging, osteoporosis, and diabetes mellitus. Osteoporos Int
2010;21:195214.
35 DeGroot J. The AGE of the matrix: chemistry, conse-
quence and cure. Curr Opin Pharmacol 2004;4:3015.
36 Vazzana N, Santilli F, Cuccurullo C et al. Soluble forms of
RAGE in internal medicine. Intern Emerg Med 2009;4:
389401.
37 Franke S, Sommer M, Ru
¨
ster C et al. Advanced glycation
end products induce cell cycle arrest and proinflammatory
changes in osteoarthritic fibroblast-like synovial cells.
Arthritis Res Ther 2009;11:R136.
38 Goldin A, Beckman JA, Schmidt AM et al. Advanced gly-
cation end products: sparking the development of diabetic
vascular injury. Circulation 2006;114:597605.
39 Steenvoorden MM, Toes RE, Ronday HK et al. RAGE
activation induces invasiveness of RA fibroblast-like
synoviocytes in vitro. Clin Exp Rheumatol 2007;
25:7402.
40 Huijberts MS, Schaper NC, Schalkwijk CG. Advanced
glycation end products and diabetic foot disease.
Diabetes Metab Res Rev 2008;24(Suppl 1):S19S24.
41 Alikhani Z, Alikhani M, Boyd CM et al. Advanced glycation
end products enhance expression of pro-apoptotic genes
and stimulate fibroblast apoptosis through cytoplasmic
and mitochondrial pathways. J Biol Chem 2005;280:
1208795.
42 Moraes do Carmo CC, Fonseca de Almeida Mela
˜
o LI,
Valle de Lemos Weber MF et al. Anatomical features of
plantar aponeurosis: cadaveric study using ultrasonog-
raphy and magnetic resonance imaging. Skeletal Radiol
2008;37:92935.
43 Jeswani T, Morlese J, McNally EG. Getting to the heel of
the problem: plantar fascia lesions. Clin Radiol 2009;64:
9319.
44 Banse X, Sims TJ, Bailey AJ. Mechanical properties of
adult vertebral cancellous bone: correlation with collagen
intermolecular cross-links. J Bone Miner Res 2002;17:
16218.
45 Reddy GK. Cross-linking in collagen by nonenzymatic
glycation increases the matrix stiffness in rabbit achilles
tendon. Exp Diabesity Res 2004;5:14353.
46 Franco R, Sa
´
nchez-Olea R, Reyes-Reyes EM et al.
Environmental toxicity, oxidative stress and apoptosis:
me
´
nage a
`
trois. Mutat Res 2009;674:322.
47 Abate M, Schiavone C, Salini V. Neoangiogenesis is
reduced in chronic tendinopathies of type 2 diabetic pa-
tients. Int J Immunopathol Pharmacol 2012;25:75731.
48 Abaci A, Og
˘
uzhan A, Kahraman S et al. Effect of diabetes
mellitus on formation of coronary collateral vessels.
Circulation 1999;99:2239
4.
49 Waltenberger
J. Impaired collateral vessel development in
diabetes: potential cellular mechanisms and therapeutic
implications. Cardiovasc Res 2001;49:55460.
50 Shoji T, Koyama H, Morioka T et al. Receptor for
advanced glycation end products is involved in impaired
8 www.rheumatology.oxfordjournals.org
Abate et al.
by guest on January 14, 2013http://rheumatology.oxfordjournals.org/Downloaded from
angiogenic response in diabetes. Diabetes 2006;55:
224555.
51 Wang SH, Sun ZL, Guo YJ et al. PPARgamma-mediated
advanced glycation end products regulation of neural
stem cells. Mol Cell Endocrinol 2009;307:17684.
52 Beeharry D, Coupe B, Benbow EW et al. Familial hyper-
cholesterolaemia commonly presents with Achilles teno-
synovitis. Ann Rheum Dis 2006;65:3125.
53 Tsouli SG, Xydis V, Argyropoulou MI et al. Regression of
Achilles tendon thickness after statin treatment in patients
with familial hypercholesterolemia: an ultrasonographic
study. Atherosclerosis 2009;205:1515.
54 Choi HK, Mount DB, Reginato AM, Pathogenesis of gout.
Ann Intern Med 2005;143:499516.
55 von Bahr S, Movin T, Papadogiannakis N et al.
Mechanism of accumulation of cholesterol and cholesta-
nol in tendons and the role of sterol 27-hydroxylase
(CYP27A1). Arterioscler Thromb Vasc Biol 2002;22:
112935.
56 Junyent M, Gilabert R, Zambo
´
nDet al. The use of Achilles
tendon sonography to distinguish familial hypercholester-
olemia from other genetic dyslipidemias. Arterioscler
Thromb Vasc Biol 2005;25:22038.
57 Abboud JA, Kim JS. The effect of hypercholesterolemia on
rotator cuff disease. Clin Orthop Relat Res 2010;468:
14937.
58 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;44:94851.
59 Siess W. Platelet interaction with bioactive lipids formed
by mild oxidation of low-density lipoprotein. Pathophysiol
Haemost Thromb 2006;35:292 304.
60 Chen R, Chen X, Salomon RG et al. Platelet activation by
low concentrations of intact oxidized LDL particles in-
volves the PAF receptor. Arterioscler Thromb Vasc Biol
2009;29:36371.
61 Artieda M, Cenarro A, Junquera C et al. Tendon
xanthomas in familial hypercholesterolemia are
associated with a differential inflammatory response
of macrophages to oxidized LDL. FEBS Lett 2005;579:
450312.
62 Matsuura F, Hirano K, Koseki M et al. Familial massive
tendon xanthomatosis with decreased high-density
lipoprotein-mediated cholesterol efflux. Metabolism 2005;
54:1095101.
63 Oosterveer DM, Versmissen J, Yazdanpanah M et al.
The risk of tendon xanthomas in familial hypercholester-
olaemia is influenced by variation in genes of the
reverse cholesterol transport pathway and the low-density
lipoprotein oxidation pathway. Eur Heart J 2010;31:
100712.
64 Beason DP, Abboud JA, Kuntz AF et al
. Cumulative
effects of hypercholesterolemia on tendon
biomechanics in a mouse model. J Orthop Res 2011;29:
3803.
65 Thiele RG, Schlesinger N. Diagnosis of gout by ultrasound.
Rheumatology (Oxford) 2007;46:111621.
66 Puig JG, de Miguel E, Castillo MC et al. Asymptomatic
hyperuricemia: impact of ultrasonography. Nucleosides
Nucleotides Nucleic Acids 2008;27:5925.
67 Schlesinger N, Thiele RG. The pathogenesis of bone
erosions in gouty arthritis. Ann Rheum Dis 2010;69:
190712.
68 Pinzur M, Freeland R, Juknelis D. The association between
body mass index and foot disorders in diabetic patients.
Foot Ankle Int 2005;26:3757.
69 Holmes GB, Lin J. Etiologic factors associated with
symptomatic achilles tendinopathy. Foot Ankle Int 2006;
27:9529.
70 Frey C, Zamora J. The effects of obesity on ortho-
paedic foot and ankle pathology. Foot Ankle Int 2007;28:
9969.
71 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:7437.
72 Warrender WJ, Brown OL, Abboud JA. Outcomes of
arthroscopic rotator cuff repairs in obese patients.
J Shoulder Elbow Surg 2011;20:9617.
73 Gaida JE, Alfredson H, Kiss ZS et al. Asymptomatic
Achilles tendon pathology is associated with a central
fat distribution in men and a peripheral fat distribution in
women: a cross sectional study of 298 individuals.
BMC Musculoskelet Disord 2010;11:41.
74 Gaida JE, Alfredson L, Kiss ZS et al. Dyslipidemia in
Achilles tendinopathy is characteristic of insulin resist-
ance. Med Sci Sports Exerc 2009;41:11947.
75 Conde J, Gomez R, Bianco G et al. Expanding the adi-
pokine network in cartilage: identification and regulation of
novel factors in human and murine chondrocytes. Ann
Rheum Dis 2011;70:5519.
76 Lago R, Gomez R, Otero M et al. A new player in cartilage
homeostasis: adiponectin induces nitric oxide synthase
type II and pro-inflammatory cytokines in chondrocytes.
Osteoarthritis Cartilage 2008;16:11019.
77 Berry PA, Jones SW, Cicuttini FM et al. Temporal rela-
tionship between serum adipokines, biomarkers of bone
and cartilage turnover, and cartilage volume loss in a
population with clinical knee osteoarthritis. Arthritis
Rheum 2011;63:7007.
78 Cilli F, Khan M, Fu F et al. Prostaglandin E2 affects pro-
liferation and collagen synthesis by human patellar tendon
fibroblasts. Clin J Sport Med 2004;14:2326.
79 Cook JL, Purdam CR. Is tendon pathology a continuum? A
pathology model to explain the clinical presentation of
load-induced tendinopathy. Br J Sports Med 2009;43:
40916.
80 Maffulli N, Longo UG, Loppini M et al. Current treatment
options for tendinopathy. Expert Opin Pharmacother
2010;11:217786.
81 Battery L, Maffulli N. Inflammation in overuse tendon
injuries. Sports Med Arthrosc 2011;19:2137.
82 Scott A, Lian R, Bahr R et al. Increased mast cell numbers
in human patellar tendinosis: correlation with symptom
duration and vascular hyperplasia. Br J Sports Med 2008;
42:7537.
83 Biancalana A, Veloso LA, Gomes L. Obesity affects
collagen fibril
diameter and mechanical properties of
tendons in Zucker rats. Connect Tissue Res 2010;51:
1718.
www.rheumatology.oxfordjournals.org 9
Tendinopathy and metabolic disorders
by guest on January 14, 2013http://rheumatology.oxfordjournals.org/Downloaded from
84 Grosicka A, Kucharz EJ. Alkaptonuria. Wiad Lek 2009;62:
197203.
85 Manoj Kumar RV, Rajasekaran S. Spontaneous tendon
ruptures in alkaptonuria. J Bone Joint Surg Br 2003;85:
8836.
86 Chua SY, Chang HC. Bilateral spontaneous rupture of the
quadriceps tendon as an initial presentation of alkapto-
nuria—a case report. Knee 2006;13:40810.
87 Carve
`
s C, Duquenoy A, Toutain F et al. Gouty tendin-
itis revealing glycogen storage disease Type Ia in two
adolescents. Joint Bone Spine 2003;70:14953.
88 Richard S, Tamas C, Sell DR et al. Tissue-specific effects
of aldose reductase inhibition on fluorescence and
cross-linking of extracellular matrix in chronic galactose-
mia. Relationship to pentosidine cross-links. Diabetes
1991;40:104956.
10 www.rheumatology.oxfordjournals.org
Abate et al.
by guest on January 14, 2013http://rheumatology.oxfordjournals.org/Downloaded from
