INTERNATIONAL JOURNAL OF IMMUNOPATHOLOGY AND PHARMACOLOGY Vol. 24, no.

I (S2), 45-50 (2011)

TENDINOPATHY AND INFLAMMATION: SOME TRUTHS

A. DEL BUONOl, MD; L. BATTERy2, BSC HONS, V. DENARO l, MD, G. MACCAUR0 2,

N. MAFFULLP, MD, MS, PHD, FRCS(ORTH)

Department ofOrthopaedic and Trauma Surgery, Campus Biomedico University ofRome,

I

Via Alvaro del Portillo, Rome, Italy.

2Department ofOrthopaedic Surgery, Catholic University ofRome, Largo Francesco Vito 1, Rome, Italy.

'Centre for Sports and Exercise Medicine, Barts and The London School ofMedicine and Dentistry, Mile
End Hospital, 275 Bancroft Road, London E1 4DG, England.

Overuse tendinopathies are a common cause of pain and disability in athletes. According to histological
findings, it is a "failed healing response" to overuse tendon injury. In obesity, macrophages and mast cells migrate
to adipose tissue, and the resulting decreased availability of immune circulating cells should be responsible
for less effective immune responses to acute tendon injury. In diabetic patients, free glucose molecules attach
to collagen, alter collagen solubility, increase resistance to enzymatic degradation, and impair cross linking,
contributing to the subsequent development of chronic tendinopathy secondary to a failed healing response to
a tendon insult. Prolonged systemic, low-grade inflammation and impaired insulin sensitivity act as a risk factor
for a "failed healing response" after an acute tendon insult, and predispose to the development of chronic overuse
tendinopathies. Further studies may reveal novel therapeutic treatment approaches.

Tendinopathies are a common cause of pain and
disability in athletes'. Most major tendons, such
as the Achilles, patellar, rotator cuff, and forearm
extensor tendons, are vulnerable to overuse, which
induces pathological changes in the tendon', The term
"tendinopathy" describes the clinical features (both pain
and pathological characteristics) associated with overuse,
in and around tendons',
Overuse tendinopathy was traditionally considered
an inflammatory status of the tendon and its adnexae,
related to frequent or excessive use', Since degenerative
change and little inflammation have been demonstrated at
histology" , the term 'tendinosis' has increasingly replaced
that of 'tendinitis '5. However, the histological descriptive
terms "tendinosis" (a degenerative pathological condition
with a lack of inflammatory change) and "tendonitis" or
"tendinitis" (implying an inflammatory process) should
be used only after histopathological confirmation", At
histology, peritendinitis and failed healing response, also
defined 'tendinosis', have increasingly allowed to consider
the overuse tendinopathy a "failed healing response"
to overuse tendon injury, with haphazard proliferation
Key words:
of tenocytes, intracellular abnormalities in tenocytes,
disruption of collagen fibers, and'a subsequent increase in
non-collagenous matrix', In tendon injuries, after failing
of the primary inflammatory response, the damage may
evolve into end stage tendinopathy". From this view point,
responsible risk factors should be investigated to prevent
this evolution. Since a high incidence oftendinopathy and
chronic low-grade systemic inflammation often concur
in obese patients with decreased insulin sensitivity, type
I, and type 2 diabetes mellitus (Tl/T2DM), such states
could be predisposing",
INFLAMMATION IN OBESITY
In obese patients with low-grade inflammation,
the detection of markedly increased plasma levels of
pro-inflammatory cytokines, such as TNF-a, IL-6,
and monocyte chemoattractant protein (MCP)-l, has
induced to hypothesize an intricate relationship between
macrophages, immune cells, and adipocyte-derived
pro-inflammatory cytokines", Different mechanisms are
supposedly involved. First of all, after MCP-l mediated

Corresponding author:
Prof Nicola Maffulli MD, MS, PhD, FRCS(Orth)
Queen Mary University of London, Barts and The London
School of Medicine and Dentistry, Centre for Sports and
Exercise Medicine, Mile End Hospital, 275 Bancroft Road,
London E I 4DG England
0394-6320 (2011)
Copyright © by BIOLIFE, s.a.s.
This publication and/or article is for individual use only and may not be further
reproduced without written permission from the copyright holder.
45 (S2) Unauthorized reproduction may result in financial and other penalties
46 (S2) A. DEL BUONO ET AL.
macrophage migration to the adipose tissue, increased
levels of pro-inflammatory cytokines, mostly TNF-a 8, and
reduced expression of adiponectin and adipocyte derived
anti-inflammatory hormones, produce local inflammation
in the adipose tissues". The altered relationship between
leptin and suppressor T cells results in increased
leptin levels, which are responsible for inhibiting the
proliferative activity and function of suppressor T cells".
On the other side, the tropism of suppressor T cells for
adipocyte reduces available systemic levels of suppressor
T cells II, and stimulates adipose tissue to produce adaptive
immune system factors, including macrophages and
mast cells", In conclusion, the amount of adipose tissue
increases the quantity of blood vessels and connective
tissue fibroblasts, fuelling the inflammatory status".
INFLAMMATION IN STATES OF IMPAIRED
INSULIN SENSITIVITY
Tendon healing is less effective in type I and type 2
diabetic patients than in normal subjects, but the reason
for this is still unclear".
Raised plasma levels of pro-inflammatory cytokines
and chemokines, as it has been found in obese patients,
induce both local and systemic insulin resistance, thus
predisposing to develop type 2 diabetes".
By discovering the insulin effects on the FOXOI
protein, it has been ascertained whether impaired
insulin sensitivity is independent from development of
chronic low-grade inflammation". FOXOI stimulates
the pro-inflammatory cytokine IL-~ but, normally, it is
physiologically inhibited by insulin. In type 2 diabetes,
endogenous insulin production and insulin levels are
normal or high in early phases, and decreases in more
advanced stages, when pancreatic compensation becomes
insufficient". Resulting increase of FOXOI and IL-~
expression, with IL-~ mediated disruption of insulin
signalling, suggests that inflammatory state and insulin
resistance may positively reinforce each another".
INFLAMMATION IN EARLY TENDINOPATHY
In acute tendon injuries, 3 phases define the healing
process", An acute inflammatory state occurs in the first
few days, generally three to seven, from the injury, with
prevalence of inflammatory cells, such as monocytes
and macrophages 14. In this phase, haematoma, platelet
activation and invasion of cells form a granuloma, and
cells migrate from the extrinsic peritendinous tissue
(tendon sheath, periosteum, subcutaneous tissue, and
fascicles), the epitenon and endotenon",
Successively, a 'proliferative phase' persists for
roughly 3 weeks after the injury. Cells proliferate and
differentiate, and migrated fibroblasts start producing
collagen (mostly collagen type III). In this way, elastic
deformation and mechanical signalling take part in the
process. Collagen type I is increasingly produced within
the tendon and its extracellular matrix, allowing repair
callus to enlarge and tendon's strength to increase, to
sustain considerable traction 10adsIO 9. Tenocytes are the
main cell type, and collagen synthesis continues for the
next five weeks, until eight weeks from the initial injury".
The Vascular Endothelial Growth Factor release facilitates
neovascularisation and stimulates the formation of
granulation tissue. In this stage, continuous, intermittent
or activity-related pain occurs" 10.
In the remodelling phase, maturation and remodelling
of collagen result in better tissue organisation and
increasing cross-linking", Callus transverse area
progressively decreases, and mechanical tissue properties
improve. Remodelling continues, taking up to a year to
complete healing". Nevertheless, tendon regeneration
is never completely achieved; hypercellularity, altered
collagen diameter, fibrils thinning result in reduced
biomechanical strength and resistance of the tendon".
DISCUSSION
Ascertaining whether a prolonged state of low-
grade systemic inflammation may influence the healing
process after an acute tendon injury, it could be noted that
tendon healing is delicate and prolonged, even when the
physiological conditions are optimal",
If minimal alterations occurs during any of the cited
healing stages, injury resolution could be longer and much
more complicated, with complete healing and resolution
could be compromised',
Investigating whether a low-grade inflammation may
influence healing stages, it has emerged that a systemic
chronic inflammatory status could disrupt the tendon
healing process.
In the first days after tendon injury, inflammatory
cells such as macrophages and monocytes migrate to the
injury site", In obese patients, the lesser availability of
circulating macrophages related to a chronic inflammatory
state could reasonably explain the less effective early
healing response",
Millar et al. examined at histology full thickness
tears of the supraspinatus tendon". Inflammatory cell
infiltrates and tear size were inversely correlated, with
markedly reduced cell types infiltrations in almost all
large tears". On the contrary, M 2 macrophages and mast
cells were detectable in specimens presenting fibroblast
hyper-cellularity", M 2 macrophages reduce inflammation
and resolve necrotic debris in the first phase, whereas they
promote angiogenesis in the proliferative stage". These
 Int. J. Immunopathol. Pharmacol. (S2) 47

Table 1. Details ofthe patients included in this series. All patients had radiation therapy as primary treatment or adjunct to surgery.

Site offracture, latency Healing of fracture,

Patients Primary tumor, site Treatment of fracture
from radiation therapy follow-up

High grade sarcoma*, left Reconstruction type

1 M,23 Left tibia, 10 years Yes; 46 months
leg intramedullary nailing

Malignant fibrous Resection and segmental

2 F,65 Left humerus, 21 years 40 months
histiocytoma, left arm prosthesis**

Metastatic lung cancer*, Reconstruction type

3 M,57 Right humerus, I year Yes; 12 months
right humerus intramedullary nailing

Multiple myeloma*, right Reconstruction type

4 F,62 Right humerus, 6 months Yes; 24 months
humerus intramedullary nailing
Non-union and nau
Metastatic breast cancer, Reconstruction type failure; revision with
5 F,47 Left femur, 7 years
left femur intramedullary nailing proximal femoral
. ?f. 1T1nnth~

Metastatic breast cancer, Proximal femoral

6 F, 76 Left femur, 20 years 14 months
left femur replacement

Multiple myeloma, right Resection and proximal

7 M,70 Right humerus, 4 months 12 months
humerus shoulder replacement

Metastatic pancreatic
8 M,69 L2-L3, 11 years Conservative 6 months
cancer, lumbar spine

Metastatic prostate cancer, Right femur (head necrosis

9 M,64 Cemented hip arthroplasty 24 months
right femur and collapse), 1 year

Metastatic breast cancer, Proximal femoral

10 F,56 Left femur, 2 years 24 months
left femur replacement

Metastatic breast cancer, Proximal femoral

11 F,34 Left femur, 13 years 20 months
left femur replacement

Metastatic breast cancer, Proximal femoral

12 F,57 Left femur, 1 year 26 months
left femur replacement

Metastatic breast cancer,

13 F,50 Left femur (head), 2 years Cemented hip arthroplasty 15 months
left femur

Hemangioendothelioma, Left femur (supracondylar),

14 M,46 Resection and arthrodesis 12 months
left patella*** 12 years

Metastatic breast cancer, Proximal shoulder

15 F,61 Left humerus, 1 year 12 months
left humerus replacement

Metastatic lung cancer,

16 M,66 Right femur (head), 4 months Cemented hip arthroplasty 8 months
right femur

Primary bone lymphoma, Proximal femoral

17 F,67 Right femur, 1 year 7 months
right femur replacement

*Combined treatment ofthe primary tumor with radiation therapy and chemotherapy
**Modular intramedullary diaphyseal segmental defect fixation system (Osteobridge IDSF System, Merete, Berlin, Germany)
***Patellectomy
48 (S2) A. DEL BUONO ET AL.
findings are indicative of post-injury "failed healing",
with matrix disorganisation, increased extracellular
ground substance, separation between collagen fibres 20.
All these detections may result in greater vulnerability to
future mechanical strain'.
These information could be useful to ascertain the
role of the mechanical overuse in the development of
tendinopathy. Mavrikakis et al. 2\, in a study on type
2 diabetic patients with shoulder tendinopathy, found
unilateral or bilateral tendinopathy in 32% of diabetic
patients, and in 10% of control those. Regarding unilateral
tendinopathy among diabetics, 45% of the tears involved
the right shoulder, while 27% the left'".
Paradoxically, long-term exposures to low levels of
physiological stress, also defined 'underloading " may
induce overload injuries", In the long term, an under-
loaded tendon may become unable to cope with the
demands imposed on it, resulting in an imbalance between
matrix metalloproteinases (MMPs) and their inhibitors
(tissue inhibitors of MMP (TIMPs), producing tendon
degradation",
Since different factors concur to determine the
etiopathogenesis and development of tendinopathy,
mechanical overuse, conceived as repetitive microtrauma,
is only a predisposing factor, acting on an already diseased
tendon- 9. This theory explains why increasing age,
athletic activity levels, and incidences oftendinopathy are
so strictly correlated'.
In large supraspinatus tears, the progressively
decreasing amount of mast cells should also be taken
into account". Such cells participate actively in tendon
healing, mostly in the later (proliferative and reparative)
phases, releasing several pro-fibrotic factors, such as
transforming growth factor (TGF)-~, IL-l, and IL-4, and
secrete mast-cell tryptase involved in the production of a
proteinase-activated-receptor-Z (PAR-2), which induces
cyclooxygenase (COX)-2- tendon proliferation and
fibrosis".
The TGF-~ pro-fibrotic action is determinant in the
development of scleroderma and other autoimmune
fibrosis-related diseases" 24. Being one of the most potent
stimulator of myofibroblasts and up-regulator of pro-
fibrotic cytokines, TGF-~ is overexpressed in biopsies
from scleroderma patients". The inhibition of some TGF-
induced pro-fibrotic cytokines eliminates the expression
of collagen I and III in scleroderma cells".
Since collagen disorganization is a typical histological
aspect of chronic tendinopathy" , it could be supposed
that reduced synthesis ofTGF-~, secondarily to decreased
mast cells availability, could compromise tendon healing,
especially if type I and III collagen are under-produced",
Concerning the TNF-a function, angiogenic and
angiostatic effects have been hypothesized". The
evidence that extracellular matrix (ECM) changes can
result in fibrotic changes, with or without a concurrent
inflammatory response, probably explains why anti-
inflammatory agents are often ineffective for the
management of scleroderma".
In addition, the lack of efficacy of anti-inflammatory
agents in patients with simultaneous inflammatory and
degenerative changes at histology!' should induce to
suspect atypical relationships between inflammation and
failed healing of chronic tendinopathy.
In obesity, chronic inflammation depends on
macrophages and mast cells migrating into adipose
tissue". Consequently, as hypothesized in high grade
supraspinatus tears", the resulting decreased availability
of immune circulating cells should be responsible for less
effective immune responses to acute tendon injury.
The administration of exogenous prostaglandins PGE 1
and PGE 2 can induce tendinopathy related changes with
an average pathological thickening of 134.1% after one
week from injection, still detectable 4 weeks later?
Since the exogenous administration ofPGE2 in human
patellar fibroblasts may reduce fibroblast proliferation and
collagen synthesis, the healing response could fail, with
disorganisation and degeneration of the cellular matrix, in
the presence of raised levels ofPGE 2 in vitro 28.
After injury, increased levels of PGE 2 and leukotriene
LTB4 could be implicated in the pathogenesis of
tendinopathy". In vivo, while high doses ofLTB 4 enhance
the catabolic effect of PGE 2 on fibroblasts, low doses of
LTB4 seemed to actually counteract PGE 2, delaying the
development of tendinopathy'". In obese and diabetic
patients, the persistently raised levels of PGE 2 and LTB4
would be involved to impair successful tendon healing.
High expression of PGE 2, COX-2 TGF-~I have also
been documented in chronic patellar tendinopathy".
Normally, in tendon injury, COX-2 is over expressed in
the active inflammatory phase, and diminishes as that
active inflammatory phase ends", However, COX-2,
acting as an inducer of PGE 2 may predispose to further
inflammation, with an abnormal resolution of the
inflammatory response, and prolonged over-expression of
inflammatory mediators responsible for typically clinical
signs of tendinopathy such as swelling, tenderness and
activity related pain".
From this standpoint, a chronic low-grade
inflammatory state may predispose and contribute to the
failed healing response implicated in the development of
tendinopathy.
When facing obese patients, lifestyle and dietary
changes can significantly reverse the systemic
inflammatory state and improve symptomatic
tendinopathy",
In patients with rotator cuff tendinopathy who are
 Int. J. Immunopathol. Pharmacol.
candidates to surgery, the surgical risk positively correlates
with increasing BMI, in both sexis".
Concerning diabetes, patients with increased
glycosylated haemoglobin were more likely predisposed
to report upper limb musculoskeletal problem, to
complain of multiple site pathology, and to have more
diabetic complications than patients with better metabolic
control",
Recently, higher fasting plasma glucose levels, within
the norrnoglycaemic range, have been observed in patients
with rotator cuff tears than those with meniscal tears".
Free glucose molecules attach to collagen, alter collagen
solubility, and increase resistance to enzymatic degradation
and impair cross linking, contributing to the subsequent
development of chronic tendinopathy secondary to a
failed healing response to a tendon insult".
Metforrnin and thiazolidine, which have anti-
inflammatory actions are commonly used for the
management of insulin resistance, in patients with obesity
and T2 diabetes, supposedly preventing complications
related to a systemic low-grade inffammation"!'.
Statins are also indicated for management of obese
individuals/T2 diabetics, and have anti-inflammatory
activity. Low-density lipoprotein (LDL) cholesterol
levels are a potential risk factor for the development of
rotator cuff tendinopathy", Statins could predispose to
the development of tendinopathy, but the pathogenetic
mechanism is still undefined".
CONCLUSION
Prolonged systemic, low-grade inflammation and
impaired insulin sensitivity act as a risk factor for a
"failed healing response" after an acute tendon insult,
and predispose to the development of chronic overuse
tendinopathies. Significant infiltration of mast cells and
macrophages suggest a role for innate immune pathways
in the events that mediate early tendinopathy. Further
mechanistic studies to evaluate the net contribution and
hence therapeutic utility of these cellular lineages and
their downstream processes may reveal novel therapeutic
treatment approaches.
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