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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 contribute 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 abnormalities have been observed in some rare congenital metabolism disorders such as alkaptonuria.
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Review doi:10.1093/rheumatology/kes395
Occurrence of tendon pathologies in metabolic
Michele Abate
, Cosima Schiavone
, Vincenzo Salini
and Isabel Andia
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.
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
Department of Medicine and Science of Aging, University G.
d’Annunzio, Chieti-Pescara, Italy and
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.
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:
Rheumatology Advance Access published January 12, 2013
by guest on January 14, 2013 from
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.
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].
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].
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.
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.
Abate et al.
by guest on January 14, 2013 from
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
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. 3
Tendinopathy and metabolic disorders
by guest on January 14, 2013 from
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.
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
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.
Abate et al.
by guest on January 14, 2013 from
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.
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].
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
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].
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 5
Tendinopathy and metabolic disorders
by guest on January 14, 2013 from
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].
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.
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%
Abate et al.
by guest on January 14, 2013 from
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].
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
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.
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.
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... Endocrine disorders are associated with joint pain and tendon injury in humans, 17,[114][115][116][117][118] and preliminary investigations in horses with PPID have shown a greater percentage of soft tissue injuries, particularly of the suspensory. 119,120 In humans, the chronic excessive circulation of glucocorticoids, commonly secondary to oral steroid treatments for COPD or autoimmune disease, can result in similar clinical signs to PPID in horses such as muscle wasting and hypertrichosis. ...
... Steroids block production of collagen and tenocyte expansion, and acute Achilles tendon rupture has been reported in humans secondary to high endogenous or exogenous levels of circulating glucocorticoids or type 2 diabetes. 13,14,114,116,117,121 In horses, the suspensory ligament was noted to be the site of greatest soft tissue injury in equine athletes overall (approx 14%), with dressage horses experiencing injury in this region > 25% of the time. 122 In addition, the suspensory ligaments of horses with PPID had a higher histology score, 119 indicating more degeneration than age-matched controls. ...
... 134 Metabolic disease is associated with joint pain in humans. 17,[114][115][116][117][118]135 It is not clear whether ID plays a role in lameness, but the fact that resveratrolbased nutritional supplements in horses have been shown to both decrease lameness and improve insulin dynamics could suggest a link. 136,137 Metabolic osteoarthritis has been documented in humans as a subtype of osteoarthritis that could also be occurring in our equine patients, and future work should investigate its occurrence. ...
Full-text available
Endocrine disorders are associated with joint pain and tendon injury in humans, but the effects in the horse are only starting to be understood. Similar patterns of clinical signs and injury appear to affect horses and humans for both orthopedic and endocrine disorders, supporting the use of a one-health approach to tackle these issues. In this Currents in One Health, we will discuss common equine endocrinopathies, current testing recommendations, dietary management, genetic predispositions, and endocrine disorders’ effects on performance. Our aim is to use a one-health lens to describe current comparative research so that veterinarians can employ cutting-edge preventative, diagnostic, and therapeutic recommendations. Identified key gaps in knowledge include whether equine metabolic osteoarthritis exists, if steroid joint injections are safe in horses with endocrine disorders, and if the return to performance percentage improves with concurrent treatment of endocrine and musculoskeletal disorders. Key takeaways include that the relationship between endocrine disorders and musculoskeletal disease in the horse goes beyond laminitis to include lameness, muscle atrophy, suspensory ligament degeneration, osteochondritis dissecans, and potentially metabolic osteoarthritis. Approaches learned from human and equine comparative studies can offer insight into injury recognition and management, thus mitigating the impact of endocrine disorders on performance in both species. Readers interested in an in-depth description of current and future research involving pathophysiology, novel interventions, and multiomic approaches to identify individuals with athletic limitations induced by endocrine disorders are invited to read the companion Currents in One Health by Manfredi et al, AJVR , February 2023.
... Кроме того, в последние несколько лет были получены данные об изменениях ахилловых сухожилий при широком спектре метаболических нарушений и заболеваний, таких как сахарный диабет (СД), гиперурикемия, ожирение, алкаптонурия и т. д. [9]. Таким образом, изменения ахилловых сухожилий по данным лучевых методов исследования являются перспективным неинвазивным маркером широкого спектра метаболических нарушений. ...
... У пациентов с определенным/вероятным диагнозом СГХС по шкале DLCN средние значения ПЗР были значимо выше в сравнении с пациентами, набравшими 5 и менее баллов -5,50 (4,10) мм ПЗР ахилловых сухожилий ПЗР ахилловых сухожилий слева, мм, Ме (ИИ) 5,20 (4,70-5,50) ПЗР ахилловых сухожилий справа, мм, Ме (ИИ) 5,10 (4,60-5,60) Средние значения ПЗР ахилловых сухожилий, мм, Ме (ИИ) 5,20 (4,60-5,50) Средние значения ПЗР ахилловых сухожилий у мужчин, мм, Ме (ИИ) 5,40 (4,80-5,90) Средние значения ПЗР ахилловых сухожилий у женщин, мм, Ме (ИИ) 5,00 (4,30) ПР ахилловых сухожилий ПР ахилловых сухожилий слева, мм, Ме (ИИ) 13,2 (12,(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)8) ПР ахилловых сухожилий справа, мм, Ме (ИИ) 13,4 (12,5-14,2) Средние значения ПР ахилловых сухожилий, мм, Ме (ИИ) 13,4 (12,3-14,4) Средние значения ПР ахилловых сухожилий у мужчин, мм, Ме (ИИ) 13,9 (12,9-14,8) Средние значения ПР ахилловых сухожилий у женщин, мм, Ме (ИИ) 13,2 (12,2-14,2) Сокращения: ИИ -интерквартильный интервал, ТКИМ -толщина комплекса интима-медиа, ОСА -общая сонная артерия, ЛОСА -левая общая сонная артерия, ПОСА -правая общая сонная артерия, ЛВСА -левая общая сонная артерия, ПВСА -правая общая сонная артерия, АСБ -атеросклеротическая бляшка, МаксСтСА -максимальный стеноз сонных артерий, СуммСтСАсуммарный стеноз сонных артерий, ПЗР -передне-задний размер, ПРпоперечный размер. ...
... против 5,00 (4,40), соответственно (p=0,04). ПР ахилловых сухожилий среди пациентов с определенным/вероятным диагнозом СГХС также был статистически значимо выше в сравнении с остальными пациентами -14,0 (12,(9)(10)(11)(12)(13)(14)(15)4) мм и 13,2 (12,(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)2) мм, соответственно (p=0,04). При проведении корреляционного анализа были выявлены взаимосвязи между ростом пациентов и ПЗР ахилловых сухожилий (r=0,34; p=0,001), ПР ахилловых сухожилий (r=0,28; p=0,009), ТКИМ левой ОСА и ПР ахилловых сухожилий (r=0,21; p=0,05), количеством АСБ и ПР ахилловых сухожилий (r=0,26; p=0,01), степенью стенозирования левой внутренней сонной артерии и ПЗР ахилловых сухожилий (r=0,22; p=0,04), стенозированием правой внутренней сонной артерии и ПЗР ахилловых сухожилий (r=0,32; p=0,002), СуммСтСА и ПР ахилловых сухожилий (r=0,27; p=0,01), МаксСтСА и ПР ахилловых сухожилий (r=0,28; p=0,007). ...
Full-text available
Aim. To assess the morphometric characteristics of Achilles tendons in patients with familial hypercholesterolemia (FH) and to identify factors associated with an increase in their size. Материали методы . Totally, 100 patients included, with severe primary hyperlipidemia, defined as an increase in total cholesterol ≥7,5 mM/L and/or lowdensity lipoprotein cholesterol ≥4,9 mM/L. All patients underwent duplex scanning of carotid arteries. Ultrasound examination of the Achilles tendons was carried out on an expert class ultrasound equipment Samsung Medison EKO 7 (Japan) with a linear sensor, frequency of 7-16 MHz. Thickness of the Achilles tendon (anteriorposterior dimension (APD)) was measured during scanning in the longitudinal section, width (transverse dimension (TD)) — scanning in the cross section. The measurements were made 2 cm proximal to the calcaneus. Results. Among the participants, 32 (32,0%) had definite/probable diagnosis of FH. In patients with definite/probable FH the mean values of APD were significantly higher in comparison with patients scored 5 or less points (DLCN) — 5,50 (4,70-6,10) mm vs. 5,00 (4,50-5,40), respectively (p=0,04). TD of Achilles tendons among this category of patients was also statistically significantly higher in comparison with the rest of patients — 14,0 (12,9-15,4) mm and 13,2 (12,2-14,2) mm, respectively (p=0,04). In correlation analysis, the relationship between the growth of patients and the APD of the Achilles tendons (r=0,34, p=0,001), the TD of the Achilles tendon (r=0,28, p=0,009), CIMT and TD of the Achilles tendons (r=0,21, p=0,05), amount of carotid plaques and TD of the Achilles tendon (r=0,26, p=0,01), total percentage of stenosis of the carotid arteries and the TD of the Achilles tendons (r=0,27, p=0,01), maximum percentage of stenosis of the carotid arteries and the TD of the Achilles tendons (r=0,28, p=0,007). According to regression analysis, factors associated with an increase in thickness of the Achilles tendons for more than 75 percentiles were male sex, diabetes mellitus, height, myocardial infarction in relatives, total percentage of stenosis of the carotid arteries and high-density lipoproteide cholesterol. Conclusion. In patients with definite/probable FH, mean values of width and thickness of the Achilles tendons were significantly higher in comparison with the rest of the patients. According to regression analysis, the factors associated with the increase in thickness of the Achilles tendons fro more than 75 percentiles were male sex, diabetes mellitus, height, myocardial infarction in relatives, total percentage of stenosis of the carotid arteries and HDL high-density lipoproteide cholesterol.
... A similar conclusion was reached by another study [15]. Age may influence the biological milieu and tendon adaptation to mechanical loading [31]. Additionally, long-term dialysis has been linked to MSK problems, including bone cysts, amyloidosis, destructive arthropathy, carpal tunnel syndrome, and spontaneous tendon rupture [32]. ...
... Tendon degeneration is often caused by metabolic disorders (e.g. diabetes, hyperuricemia, or hypercholesterolemia) [31]. Hypercholesterolemia may be associated with abnormal tendon thickness or structure [34]. ...
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Background There is no much information about the entheseal involvement among hemodialysis (HD) patients. The aim of this study was to assess the frequency and distribution of ultrasonographic (US) entheseal alterations in HD patients and to evaluate the association between US abnormalities and both clinical and laboratory data. Methods This study was conducted on 41 HD patients and 23 sex- and age- matched controls. All participants were evaluated clinically for any signs of enthesopathy. Six entheses sites were scanned bilaterally using grey scale (GS) and power Doppler (PD) US and were scored using Madrid Sonography Enthesitis Index (MASEI) scoring system. Results In HD patients, at least one clinical sign suggestive of enthesopathy was found in 69 (14%) of 492 entheses. HD patients had statistically significant higher scores of structural tendon abnormalities (p < 0.001), enthesis thickening (p < 0.001), bone erosions (p < 0.001) and calcification (p = 0.037) than the healthy controls. Total MASEI score was higher in HD patients than healthy controls (median;18 vs 8, p < 0.001), also, MASEI-inflammatory (median;11 vs 3, p < 0.001) and damage scores (median;6 vs 0, p < 0.001). There was a statistically significant positive association between total MASEI score and both age (p = 0.032) and duration of HD (p = 0.037). Duration of HD was predictive for both MASEI-damage component (p = 0.004) and total MASEI score (p = 0.014). Conclusion There is a high prevalence of subclinical enthesopathy in HD patients. The entheseal US alterations is much higher in HD patients than in healthy subjects. The duration of HD is the significant predictor of enthesopathy in HD patients.
... A similar conclusion was reached by another study [15]. Age may in uence the biological milieu and tendon adaptation to mechanical loading [31]. Additionally, long-term dialysis has been linked to MSK problems, including bone cysts, amyloidosis, destructive arthropathy, carpal tunnel syndrome, and spontaneous tendon rupture [32]. ...
... Tendon degeneration is often caused by metabolic disorders (e.g. diabetes, hyperuricemia, or hypercholesterolemia) [31]. Hypercholesterolemia may be associated with abnormal tendon thickness or structure [34]. ...
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Background Musculoskeletal (MSK) complications are one of the most common health concerns that impact individuals on maintenance hemodialysis (HD). However, little is known about the entheseal involvement in HD patients. The aim of this study was to assess the prevalence and distribution of entheseal ultrasonographic (US) alterations in HD patients and to evaluate the association between US findings and both clinical and laboratory data. Methods: This study was conducted on 41 HD and 23 sex- and age- matched controls. All HD patients and healthy controls were evaluated clinically to detect any clinical evidence of enthesopathy. Six entheses sites were scanned bilaterally using grey scale (GS) and power Doppler (PD) ultrasonography (US) and were scored using Madrid Sonography Enthesitis Index (MASEI) scoring system. Results: Clinical examination revealed at least one sign suggestive of enthesopathy in 69 (14.02) of 492 entheses in 41 HD patients. HD patients had statistically significant higher scores of stuctural tendon abnormalities (p<0.001), enthesis thickening (p<0.001), bone erosions (p<0.001) and calcification (p=0.037) than healthy controls. Total MASEI score was higher in HD patients than healthy controls (median ;18 vs 8, p<0.001), also, MASEI-inflammatory (median ;11 vs 3, p<0.001) and damage scores (median ;6 vs 0, p<0.001). There was a statistically significant positive association between total MASEI score and both age (p=0.032) and duration of HD (p=0.037). Duration of HD was predictive for both MASEI-damage component (p=0.004) and total MASEI score (p=0.014). Conclusions: There is a high prevalence of asymptomatic enthesopathy in HD patients. The burden of entheseal US alterations is much higher in HD patients than in healthy subjects. US can be helpful in the early detection of entheseal abnormalities. The duration of HD is the most significant predictor of enthesopathy in HD patients.
... Inflammation of this region, known as enthesitis, can be a clinical manifestation of underlying inflammatory disorders such as spondyloarthropathies (10). Traumatic, mechanical overuse and metabolic conditions can also cause pathologic changes at the enthesis (11,12). Among all aetiologies of enthesitis, one of the most commonly involved sites is the Achilles tendon enthesis (13)(14)(15). ...
Objectives: Ultrasound evaluation of the Achilles tendon has been utilised to assess involvement at the entheses in the setting of various inflammatory, metabolic, and mechanical processes. The purpose of this systematic review was to evaluate the differences in ultrasound findings at the Achilles enthesis between inflammatory tendinopathy (IT) versus non-inflammatory tendinopathy (NIT). Methods: A review of all studies involving ultrasound evaluation of IT or NIT (mechanical or metabolic) affecting the Achilles enthesis was performed by searching the Embase, PubMed and Medline databases from start until October 2020. We assessed study quality and extracted summary data from each individual study. We used random-effects meta-analysis to determine the average proportion of affected anatomic sites across all studies for each abnormality, weighting the analysis based on the size of each individual study. Results: Achilles enthesis thickening was more frequent in the symptomatic IT (sIT) group (37.8%) compared to the unspecified IT (25%), NIT (11.2%) and healthy control (2.7%) groups. Increased vascularity at the enthesis was more common in the NIT (23.4%) group compared to the IT (9%), sIT (8.6%) and healthy control (0.1%) groups. Erosions were more common among the IT (17.3%) and sIT (14%) groups compared to the NIT (2.2%) and healthy controls (0.3%) groups. Conclusions: While Achilles enthesis thickening, Doppler signal and calcaneal erosions discriminate IT from healthy subjects, erosions are more likely to distinguish IT from NIT than thickening or Doppler signal. Additional study is needed to quantify the diagnostic performance of ultrasound at this location given the frequency of abnormalities in NIT.
... 32,33 This condition promotes a state of low-grade inflammation called metaflammation, 31 with shifting of the phenotype of macrophages, and dysfunction and reduction of T regulatory cells. 3,6,16,28,[34][35][36] Moreover, metaflammation state is a well-recognized risk factor for the development of the metabolic syndrome, characterized by different dysmetabolic conditions, such as type 2 diabetes, hypertension and hypercholesterolemia. 37 Leptin, a major pro-inflammatory adipokine, is secreted from adipocytes and regulates several physiological behaviours such as satiety, appetite and food intake. 38 In particular, leptin seems to increase anorexigenic and decrease orexigenic peptide synthesis in the hypothalamus, causing a reduction of appetite. ...
Background The aetiopathogenesis of tendinopathy is uncertain, but inflammation may play a role in the early phase of tendinopathy and in tendon healing response. We investigated the most up-to-date evidence about the association between obesity, high-fat diet and tendinopathy, focusing on the role of adipokines, inflammatory pathways and molecular changes. Sources of data A systematic review was performed searching PubMed, Embase and Cochrane Library databases following the PRISMA guidelines. We included studies of any level of evidence published in peer-reviewed journals. The risk of bias (SIRCLE) was assessed, as was the methodological quality (CAMARADES) of the included studies. We excluded all the articles with a high risk of bias and/or low quality after the assessment. After applying the inclusion and exclusion criteria, we included 14 studies of medium or high quality. Areas of agreement A high-fat diet negatively affects tendon quality, increasing the risk of rupture and tendinopathy. Areas of controversy Controversial evidence exists on both tendon fat infiltration secondary to a dysregulation of the lipid metabolism and of a molecular effect of inflammatory pathways. Growing points The secretion of adipokines is strictly related to fat ingestion and body composition and can potentially act on tendon physiology and injury. Areas timely for developing research Adipokines, low-grade inflammation and fat intake play a role in disrupting tendon healing and setting up tendinopathy. Further high-quality research is needed to better define the molecular pathways involved.
... The paper by Falsetti et al. (3) shows an even higher prevalence of US findings indicative of enthesitis, according to the OMERACT criteria, in a group of patients with metabolic syndrome. Healthy subjects with a known history of metabolic syndrome were excluded from our study as the entheses, as well as the tendons, are anatomic areas which are frequently affected in these conditions (4,5). Similar to our study, the authors found a very low prevalence of PD signal at the enthesis (1% of the entheses examined), suggesting that PD signal might represent a reliable US biomarker of "active" inflammation. ...
... The most common tendon disorders involve the Achilles, patellar, rotator cuff, digital flexor, and elbow extensor tendons, often leading to despair for patients and frustration for the clinicians trying to treat them [4][5][6] . Unfortunately, the societal prevalence of tendon disorders is only increasing, in line with major risk factors including age, obesity, diabetes, mechanically demanding work and sport activities [7][8][9][10][11][12][13] . Yet despite ever-growing rates of incidence, substantial individual suffering, and an enormous collective socioeconomic burden, tendon disorders remain under-researched and poorly understood 5 . ...
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Background: Tendon disorders increasingly afflict our aging society but we lack the scientific understanding to clinically address them. Clinically relevant models of tendon disease are urgently needed as established small animal models of tendinopathy fail to capture essential aspects of the disease. Two-dimensional and three-dimensional cell and tissue culture models are similarly limited, lacking many physiological extracellular matrix cues required to maintain tissue homeostasis or guide matrix remodeling. These cues reflect the biochemical and biomechanical status of the tissue, and encode information regarding the mechanical and metabolic competence of the tissue. Tendon explants overcome some of these limitations and have thus emerged as a valuable tool for the discovery and study of mechanisms associated with tendon homeostasis and pathophysiology. Tendon explants retain native cell-cell and cell-matrix connections, while allowing highly reproducible experimental control over extrinsic factors like mechanical loading and nutritional availability. In this sense tendon explant models can deliver insights that are otherwise impossible to obtain from in vivo animal or in vitro cell culture models. Purpose: In this review, we aimed to provide an overview of tissue explant models used in tendon research, with a specific focus on the value of explant culture systems for the controlled study of the tendon core tissue. We discuss their advantages, limitations and potential future utility. We include suggestions and technical recommendations for the successful use of tendon explant cultures and conclude with an outlook on how explant models may be leveraged with state-of-the-art biotechnologies to propel our understanding of tendon physiology and pathology.
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Achilles tendon xanthoma (ATX) is one of the typical features of familial hypercholesterolemia (FH). The morphological evaluation of ATX by X-ray radiography is widely recognized; however, the utility of other imaging modalities remains unclear. We herein report two cases of FH in which Doppler ultrasound imaging demonstrated a microvascular flow in ATX that only rarely could be observed in normal Achilles tendons. Neoangiogenesis accompanies chronic inflammation and it may play an important role in the deposition of cholesterol crystals leading to ATX. In addition to the morphological evaluation of ATX, the assessment of neoangiogenesis may therefore be essential for the evaluation of ATX.
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Introduction: Diabetes mellitus (DM) and osteoporotic fractures are major causes of mortality and morbidity in older subjects. Recent reports have revealed close association between fracture risk and DM types 1 and 2 (DM1 and DM2, respectively). Aim of this review is to highlight the importance of these diseases in the elderly and examine certain etiopathogenetic aspects of DM-associated osteoporosis, which could be useful in management of diabetic patients. Materials and methods: We searched the Embase and PubMed databases using diabetes, osteoporosis, and bone mineral density (BMD) as search terms and 1989-2009 as publication dates. Discussion: The risk of fractures seems to be increased in both types of DM although DM2 seems to be associated with normal-high BMDs compared with the normal population. This apparent paradox could reflect greater bone frailty in diabetic patients that are unrelated to adipose tissue, hyperinsulinemia, deposition of advanced glycosylation end products in collagen, reduced serum IGF-1 levels, hypercalciuria, renal failure, microangiopathy, and/or inflammation. Diabetic patients' propensity to fall and multiple comorbidities might also explain their higher fracture rates. The effects of drugs that inhibit bone resorption in diabetic patients are probably similar to those obtained in nondiabetics although there is little information on this issue. In general, effective treatment of diabetes has positive effects on bone metabolism. Metformin acts directly on bone tissue, reducing AGE accumulation, and insulin has direct effects on osteoclast activity. In contrast, the thiazolidinediones seem to have negative effects since they orient mesenchymal progenitor cell differentiation toward adipose rather than bone tissue. Incretin therapy is a newer approach that appears to modify interactions between nutrition and bone turnover (e.g., postprandial suppression of bone resorption). Conclusions: Better understanding of how diabetes and its treatment influence bone tissue could lead to more effective strategies for preventing fractures in diabetic patients. More investigation is needed to determine whether conventional osteoporotic therapy is fully effective in patients with DM.
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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 histopathological 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.
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Tendinopathy refers to the clinical presentation of activity-related pain, focal tendon tenderness, and intratendinous imaging changes. The underlying pathology was once thought to be due to inflammation ('tendinitis'), but is now considered to predominantly result from degeneration ('tendinosis'). While some progress has been made in understanding tendinosis, the condition remains poorly understood and a need exists for suitable exploratory preclinical models. It is unlikely that one suitable model exists because of the complexity of the underlying pathology and myriad of possible causes. This paper provides an overview of current models utilized in tendinopathy research. It progresses hierarchically from in vitro and ex vivo models to in vivo models. For each model, rationale for use, pertinent findings, and advantages and disadvantages are discussed. By improving on these models, new methods for the prevention and treatment of tendinopathy may be explored with the ultimate outcome being a reduction in the occurrence and effects of the condition in humans.
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Tendons transmit skeletal muscle forces to bone and are essential in all voluntary movement. In turn, movement appears to affect tendon properties, and in recent years considerable effort has been put into discovering how tendon tissue responds to mechanical stimuli in vivo. Months and years of mechanical loading can influence the gross morphology of tendon, seen as an increase tendon cross sectional area (CSA). Similarly, tendon stiffness appears to be affected by weeks to months of loading. Increased stiffness can relate to changes in CSA and/or tendon material properties (modulus), though the relative contribution of these parameters is largely unclear. The possible mechanisms behind alterations in tendon material properties include changes in collagen fibril morphology and levels of cross-linking between collagen molecules. Furthermore, increased levels of collagen synthesis and expression are seen as a response to acute exercise and training, and may be a central parameter in tendon adaptation to loading. There are indications that this collagen-induction relates to the auto-/paracrine action of collagen-stimulating growth factors, such as TGFβ-1 and IGF-I, which are expressed in response to mechanical stimuli.
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A major feature of chronic tendinopathy is a change in the nature and organisation of the extracellular matrix of tendon. Increased levels of proteoglycans have been shown in the extracellular matrix of tendinopathic tendons and these appear to influence the increased hydration and swelling of the tissue that is a feature of this condition. There is a paucity of knowledge about proteoglycans in normal and tendinopathic tendons. This review sets out to describe the nature, function and metabolism of proteoglycans present in normal tendon and in tendinopathy and outlines how changes in proteoglycan metabolism may contribute to the development and progression of this disease.
In diabetes, the prevalence of tendon degeneration is increased. As neoangiogenesis is impaired in several diabetic complications, the aim of this study is to evaluate the neovessel formation in tendinopathies. Patients aged more than 55 years were selected, and divided into two groups: a) type 2 diabetic patients, and b) non-diabetic subjects. In both groups, those with ultrasound features of tendinopathy were included, and intratendinous vascularisation was estimated by means of Power Doppler. Ultrasound features of tendinopathy were observed in 104 diabetic subjects and in 221 controls. Neovascularisation, with higher Power Doppler scores, was found more frequently in controls, while lower Power Doppler scores were prevalent in diabetic subjects. In subjects with diabetes, tendinopathic features are significantly higher than healthy controls, while the prevalence of neovascularization inside tendons is less represented.
Apoptosis is an evolutionary conserved homeostatic process involved in distinct physiological processes including organ and tissue morphogenesis, development and senescence. Its deregulation is also known to participate in the etiology of several human diseases including cancer, neurodegenerative and autoimmune disorders. Environmental stressors (cytotoxic agents, pollutants or toxicants) are well known to induce apoptotic cell death and to contribute to a variety of pathological conditions. Oxidative stress seems to be the central element in the regulation of the apoptotic pathways triggered by environmental stressors. In this work, we review the established mechanisms by which oxidative stress and environmental stressors regulate the apoptotic machinery with the aim to underscore the relevance of apoptosis as a component in environmental toxicity and human disease progression.
Previous research has shown that plantar fascia and Achilles tendon thickness is increased in diabetes. The aims of present study were to assess whether tendon changes can occur in the early stages of the disease and to evaluate the extent of the influence of body mass index (BMI). The study population included 51 recent-onset type II diabetic subjects, who were free from diabetic complications, divided according to BMI into three groups (normal weight, overweight, and obese). Eighteen non-diabetic, normal-weight subjects served as controls. Plantar fascia and Achilles tendon thickness was measured by means of sonography. The groups were well balanced for age and sex. In all the diabetic subjects, plantar fascia and Achilles tendon thickness was increased compared to the controls (p < 0.001, p = 0.01, p = 0.003, respectively). A significant relationship was found between plantar fascia thickness and BMI values (r = 0.749, p < 0.0001), while the correlation between BMI and Achilles tendon was weaker (r = 0.399, p = 0.004). This study shows that plantar fascia and Achilles tendon thickness is increased in the early stages of type II diabetes and that BMI is related more to plantar fascia than Achilles tendon thickness. Further longitudinal studies are needed to evaluate whether these early changes can overload the metatarsal heads and increase the stress transmitted to plantar soft tissues, thus representing an additional risk factor for foot ulcer development.
Different tendons are designed to withstand different mechanical loads in their individual environments. Variable physiologic loading ranges and correspondingly different injury thresholds lead to tendon heterogeneity. Also, tendon heterogeneity is evident when examining how different tendons regulate their response to changes in mechanical loading (over- and under-loading). The response of tendons to changes in mechanical loading plays an important role in the induction and progression of tendinosis which is tendon degeneration without inflammation. Tendon overuse injury is likely related to abnormal mechanical loading that deviates from normal mechanical loading in magnitude, frequency, duration and/or direction. Mechanical loading that results in tendon overuse injury can initiate a repair process but, after failed initial repair, non-resolving chronic attempted repair appears to lead to a "smoldering" fibrogenesis. Contributions of regulatory components, including minor components in the "nerve-mast cell-myofibroblast axis", are key features in the development and progression of tendinosis. Hormonal and genetic factors may also influence risk for tendinosis. Further understanding of how tendinosis induction is related to mechanical use/overuse, how tendinosis progression is related to abnormal regulation of attempted repair, and how induction and/or progression are modulated by other risk factors may lead to interventions that mitigate risk and enhance functional repair.
Rotator cuff tears are common orthopedic injuries and their arthroscopic treatment can be technically challenging. This study evaluated the outcomes of arthroscopic rotator cuff repairs in obese patients. We hypothesized that there would be a direct correlation between worse outcomes of arthroscopic rotator cuff repairs and increasing body mass index (BMI). A retrospective review of patients undergoing arthroscopic rotator cuff repair by one orthopedic surgeon between 2005 and 2008 was performed. The study included 149 rotator cuff repairs. Recorded data included age, sex, BMI, size of rotator cuff tear on magnetic resonance imaging and intraoperatively, number of anchors used for repair, functional outcomes (American Shoulder and Elbow Surgeons and University of Pennsylvania scores), surgery time, total time for anesthesia, positioning, and hospital stay. Tears were classified by size. Strict inclusion and exclusion criteria were used. Surgical procedures were performed with general anesthesia, interscalene block, beach chair positioning, and a standardized operative technique. Patients followed a standard postoperative rehabilitation protocol. Mean patient age was 66 years. Mean follow-up was 16.3 months. Tears were classified as high grade partial (12%), small (23%), medium (29%), large (22%), and massive (14%). Patients were classified as normal weight (38%), overweight (23%), obese (20%), and morbidly obese (19%). A statistically significant correlation was found between obesity and worse functional outcomes, longer operative times, and longer length of hospital stay. This study reports new data concerning the association of BMI and early clinical outcome after arthroscopic rotator cuff repair surgery. Even though the obese group had greater limitations and lower rates of satisfaction at final follow-up than their non-obese counterparts, they still reported significant improvements from the surgery. Obesity has a negative impact on the operative time of arthroscopic rotator cuff repairs, length of hospitalization, and functional outcomes.