Mini-review

Received: 1 June 2017 Revised: 1 September 2017 Accepted article published: 8 September 2017 Published online in Wiley Online Library:

(wileyonlinelibrary.com) DOI 10.1002/jsfa.8664

Anti-inflammatory effects of polyphenols in

arthritis
Francesca Oliviero,a* Anna Scanu,a Yessica Zamudio-Cuevas,b
Leonardo Punzia and Paolo Spinellac

Abstract
Polyphenols have been extensively investigated with regard to their antioxidant, anti-inflammatory, and immunomodulant
properties in many inflammatory chronic conditions. The aim of this review is to summarise how these compounds can modulate
the inflammatory pathways which characterise the most prevalent arthropathies including osteoarthritis, rheumatoid arthritis
and crystal-induced arthritis. Among polyphenols, epigallocatechin gallate, carnosol, hydroxytyrosol, curcumin, resveratrol,
kaempferol and genistein have been the most widely investigated in arthritis. The most important results of the studies
outlined in this article show how polyphenolic compounds are able to inhibit the expression and the release of a number of
pro-inflammatory mediators and proteolytic enzymes, the activity of different transcriptional factors and the production of
reactive oxygen species in vitro. Studies on animal models of rheumatoid arthritis, osteoarthritis and gout show interesting
results in terms of reduced tissue damage, restored cartilage homeostasis, and decreased levels of uric acid, respectively.
Despite the multiple protective effects of polyphenols, there are no dietary recommendations for patients affected by rheumatic
diseases. Future studies, including intervention trials, should be conducted to determine the relevance of polyphenols
consumption or supplementation in arthritis.
© 2017 Society of Chemical Industry

Keywords: polyphenols; inflammation; osteoarthritis; rheumatoid arthritis; crystal-induced arthritis

INTRODUCTION diseases. Among these factors, polyphenols have been extensively

The value of diet in the maintenance of healthy conditions and
well-being has been largely emphasised in the last decades. Wide
epidemiological studies have demonstrated that many chronic,
aggressive, at times deadly diseases, such as cancer and cardio-
vascular diseases, can be associated with particular dietary habits.1
However, it is unlikely that a single food item, consumed for a short
time, could be able to trigger a disease or to prevent it. More gen-
erally, a whole range of dietary components, consumed over a
long time period, could significantly affect human health. In this
context the Mediterranean diet represents one of the healthiest
dietary models, thanks, in particular, to a combination of healthy
food intake and a proper life style.2
Arthritis encompasses a heterogeneous group of diseases
mainly characterised by articular damage, inflammation, pain
and disability. The most prevalent forms are osteoarthritis (OA),
rheumatoid arthritis (RA), spondyloarthritis (SpA), crystal-induced
arthritis and systemic lupus erythematosus (SLE). Although differ-
ent risk factors are involved in their development, these diseases
share common chronic inflammatory features which lead to
increased morbidity and mortality. Pharmacological treatment is
based on non-steroidal anti-inflammatory drugs (NSAIDs), cor-
ticosteroids, immunosuppressants and the more recent costly
biological drugs. However, while the specificity of the therapeutic
targets and the effectiveness of the therapies have shown an
increase in RA, SpA and SLE, actually there are no treatment able
to slow down or to prevent articular destruction in OA.
It has been demonstrated that nutritive and non-nutritive
dietary factors can affect the clinical outcome of rheumatic
investigated with regard to their antioxidant, anti-inflammatory
and immunomodulant properties.
The current article discusses how these plant-derived natu-
ral compounds can modulate the inflammatory pathways which
characterise the most prevalent arthropathies. Studies investigat-
ing the effect of different polyphenols in cartilage degradation
and synovitis are outlined hereafter, with particular emphasis on
inflammatory mediators involved in joint destruction.
POLYPHENOLS IN OSTEOARTHITIS
Osteoarthritis is the most prevalent joint disease worldwide. It is
characterised by deteriorative structural changes in the cartilage,
leading to pain, loss of joint function, and disability. Although
OA is not included among inflammatory diseases, increasing evi-
dence indicates that inflammation plays a central role in OA
∗ Correspondence to: F Oliviero, Rheumatology Unit, Department of
Medicine – DIMED, University of Padova, via Giustiniani, 2, 35128 Padova,
Italy. E-mail: francesca.oliviero@unipd.it
a Rheumatology Unit, Department of Medicine – DIMED, University of Padova,
Italy
b Laboratorio de Líquido Sinovial, Instituto Nacional de Rehabilitación “Luis
Guillermo Ibarra Ibarra”, Mexico City, Mexico
c Clinical Nutrition Unit, Department of Medicine – DIMED, University of Padova,
ltaly

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Table 1. Main polyphenolic compounds investigated in osteoarthritis and their effects demonstrated in the different cellular or animal model
Polyphenol Model
EGCG Chondrocytes
Mononuclear cells, Fibroblast-like cells
Animal model
Curcumin Animal model
Carnosol Chondrocytes
Hydroxytyrosol Chondrocytes
Animal model
PG, prostaglandins; NO, nitric oxide; TNF, tumor necrosis factor; CK, cytokines; CMK, chemokines; ROS, reactive oxygen species; iNOS, inducible NO
synthase; COX, cyclooxygenase.
pathogenesis.3 Chondrocytes are the key players in OA. These
cells compose the articular cartilage and are responsible for the
secretion and the turnover of the components of the extracellular
matrix, such as proteoglycans and type II collagen, and therefore
are crucial to maintain its homeostasis. During the development
of OA, chondrocytes undergo phenotypic and signalling transduc-
tion changes that compromise cartilage integrity and sustain the
progression of the disease. They decrease the synthesis of extra-
cellular matrix components, and increase that of proteases [e.g.
metalloproteases (MMPs) and A Disintegrin and Metalloproteinase
with Thrombospondin motifs (ADAMTs)], nitric oxide and other
pro-inflammatory mediators.3
Studies investigating the role of polyphenols in the OA pro-
cess focus, for the most part, on their chondroprotective effect,
in terms of reduced catabolic response following cell stimula-
tion. Among polyphenolic compounds, epigallocatechin gallate
(EGCG), carnosol, hydroxytyrosol (HT), procyanidin and curcumin
have been the most widely investigated in OA (Table 1).
EGCG, the most abundant and powerful catechin in green tea,
has been demonstrated to possess marked anti-inflammatory
properties in vitro as it inhibits the production of prostaglandin
(PG) E2 and nitric oxide (NO) and the activation of the nuclear
factor kappa B (NF-𝜅B) in interleukin-1𝛽 (IL-1𝛽)-stimulated
chondrocytes.4,5 The chondroprotective effects of EGCG have
been noted with regard to the catabolic response induced by
advanced glycation end products (AGEs), molecules known to
accumulate during the ageing process and which have been
supposed to have a role in OA development.6 AGE-stimulated
cells treated with EGCG have been shown to reduce the expres-
sion of tumour necrosis factor (TNF) along with a decreased
translocation and activation of NF-𝜅B.7 The anti-catabolic effect
of EGCG has also been demonstrated in animal models of OA
with regard to the inhibition of proteolytic enzymes such as the
proteases MMP-13 and ADAMTS-5 which represent important
mediators of cartilage destruction, as discussed above.8 Another
important anti-inflammatory effect exerted by EGCG has been
demonstrated in OA fibroblast-like synoviocytes (FLSs) and mono-
cytes stimulated with calcium crystals which, in patients with
OA, contribute to synovial inflammation and are associated with
a more aggressive disease. In this model EGCG has been found
to inhibit the release of cytokines such as IL-1𝛽, IL-8, (C-C motif )
ligand 2 (CCL2) and transforming growth factor-𝛽 (TGF-𝛽), while a
role for EGCG in interfering with membrane organisation has also
been highlighted.9
Similarly to EGCG, curcumin is another bioactive polyphenol
found in the spice turmeric, which has been largely studied as
a cancer preventive, anti-inflammatory and antioxidant agent.
wileyonlinelibrary.com/jsfa © 2017 Society of Chemical Industry
F Oliviero et al.
Actions
↓ PG, NO, TNF ↓ Transcriptional factors
↓ CK, CMK
↓ Proteolytic enzymes
↓ Clinical indices ↓ Systemic oxidative stress
↓ Proteolytic enzymes ↑ Cartilage matrix components ↓ CK, PG
↓ ROS, iNOS, COX-2 ↓ Proteolytic enzymes ↑ Autophagy
↓ Disease severity
Curcumin has shown important chondroprotective effects and
anti-catabolic activities in OA.10 Oral administration of curcumin
has been significantly found to slow down disease progression
in a post-traumatic OA mouse model through the reduction of
synovitis, proteoglycan loss, cartilage erosion and the expression
of adipokines and pro-inflammatory mediators.11 Clinical studies
carried out on patients with OA have shown beneficial effects in
terms of clinical indices and systemic oxidative stress.12,13
In recent years increasing attention has been paid to the bene-
ficial effect of carnosol, a polyphenolic compound found in rose-
mary, sage and other aromatic Mediterranean herbs.
Carnosol has been demonstrated to inhibit pro-inflammatory
and catabolic mediators of cartilage breakdown in chondrocytes
and to promote an increase in cartilage matrix formation com-
ponents, such as aggrecan and type II collagen.14 Interestingly,
that study showed an important inhibitory effect of carnosol on
IL-6 and PGE2 production.14 Similar effects have been observed
in murine lipopolysaccharide (LPS)-stimulated macrophages
and human IL-1𝛽-stimulated chondrocytes confirming a role
for carnosol in regulating acute and chronic inflammatory
processes.15
Among the polyphenols furnished by the Mediterranean dietary
habit, those contained in extra-virgin olive oil (EVOO), such as HT,
have been tested in OA models with interesting results.16 A pro-
tective effect of HT has been observed in human chondrocytes
under oxidative stress conditions. Hydroxytyrosol prevented accu-
mulation of reactive oxygen species (ROS) as well as the increase
in inducible nitric oxide synthase.
(iNOS), cyclooxygenase-2 (COX-2), and MMP-13 gene expression.
Through the induction of autophagy, HT has been shown to
protect cells from DNA damage and cell death.16 An extract of olive
and grape seeds, standardised according to HT and procyanidins
content, has been used in animal models of post-traumatic OA
showing a decrease in the severity of the disease and an overall
anti-IL-1𝛽 effect.17
The results of the studies outlined above suggest that natural
compounds able to alter the catabolic response to external stimuli
in OA could be useful not only to contrast cartilage breakdown
but also to slow down the low-grade chronic inflammation which
occurs in this disease.
POLYPHENOLS IN RHEUMATOID ARTHRITIS
Rheumatoid arthritis represents the most common inflammatory
joint disease in women. It is characterised by severe synovitis,
infiltration of lymphocytes and plasma cells in the synovial tissue.
A typical pannus, which forms by the proliferation of FLSs, invades
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Table 2. Main polyphenolic compounds investigated in rheumatoid arthritis and their effects demonstrated in the different cellular or animal model

Polyphenol Model Actions

Curcumin Fibroblast-like cells ↑ Apoptosis, caspases

↓ COX-2, PG, CK
↓ Transcriptional factors
AIA in rats ↓ Transcriptional factors
↓ CK
Resveratrol CIA in mice ↓ Th17 cell numbers,
↓ CK
Fibroblast-like cells ↓ CK
↓ MMPs
AIA in rats ↓ RA biomarkers
↑ IL-10, GSH
Hydroxytyrosol AIA in rats ↓ Disease scores
↓ CK
CIA in mice ↓ Kinases, transcriptional factors
↓ COX-2
Genistein CIA in mice and rats ↓ Collagen II autoantibodies, IFN-𝛾
↑ IL-4
= Th1/Th2 balance
Fibroblast-like cells ↓ CK, ROS, MMPs
EGCG Fibroblast-like cells ↓ CK, CMK, MMPs
↓ Kinases phosphorylation, transcriptional factors
CIA in mice ↑ Nrf-2 activation
Kaempferol Fibroblast-like cells ↓ Proliferation, MMPs, COX-2, PG
↓ Kinase phosphorylation
↓ NF-𝜅B activation
Emodin Fibroblast-like cells ↓ Histone deacetylase 1 activation
↓ CK, PG, MMPs
CIA in mice ↓ Osteoclast differentiation, transcriptional factors
↓CK, COX-2, PG, MMPs

AIA, antigen-induced arthritis; CIA, collagen-induced arthritis; PG, prostaglandins; CK, cytokines; CMK, chemokines; ROS, reactive oxygen species; COX,
cyclooxygenase; IFN, interferon; RA, rheumatoid arthritis; MMPs, metalloproteases; GSH, glutathione.

the subchondral bone and destroys the cartilage with subsequent
irreversible ankyloses.18
Polyphenols have been found to have potential beneficial activ-
ities in RA because of their numerous properties able to interfere
with specific disease pathways (Table 2).19
As the synovium is the principal target of inflammation in RA and
the resident FLSs are implicated in the pathogenesis of synovitis,
most of the studies regarding polyphenols focus on the response
of these cells after being activated and challenged with these
compounds. Their effect has been investigated, in particular, on
the secretion of MMPs, cytokines and growth factors and on those
mechanisms that contribute to the loss of normal homeostasis in
the synovial joint and lead to bone erosion.20
Several studies have been carried out using animal models of
RA, such as adjuvant-induced and collagen-induced arthritis (CIA),
which are very useful to reproduce the main pathological features
of the disease and to investigate the effect of pharmacological
and non-pharmacological substances targeting the inflamed
synovium.
Among polyphenols, those found in spices have shown to be
effective in these animal models by increasing/decreasing the
production of anti-inflammatory/pro-inflammatory cytokines,
respectively, and activating the antioxidant defence system.21 – 23
Curcumin, in particular, has shown an interesting preventive effect
having been shown to be more effective on disease onset rather
than disease progression. In vitro, curcumin has been demon-
strated to exert an anti-proliferative and anti-inflammatory action
in RA-FLS by inducing apoptosis and causing the inhibition of the
COX-2 pathways which lead to PGE2 production.24 Additionally,
the exposure of the RA-FLS to curcumin resulted in the decrease of
cytokines and growth factors, such as IL-6 and vascular endothelial
growth factor (VEGF), and the deactivation of NF-𝜅B and extracel-
lular signal–regulated kinase (ERK1/2) inflammatory pathways.25
As reported for other substances in this paragraph, the influ-
ence of polyphenols on specific signal transduction pathway is
an interesting point as the sustained activation of these pathways
may alter the threshold for immune activation in RA. Furthermore,
many cytokine receptors signal via common kinases whose inhi-
bition by polyphenols can lead to the simultaneous reduction of
several cytokines. An example is provided by the use of inhibitors
of Janus kinase–signal transducer and activator of transcription
(JAK/STAT) and mitogen-activated protein kinases (MAPKs) which
block the activities of a broad range of cytokines.26
The beneficial properties of curcumin have been supported by
a randomised clinical trial demonstrating that patients with RA
receiving this polyphenol showed an improvement in disease
activity similar to that obtained with diclofenac.27
Resveratrol, a polyphenol mainly contained in grape juice, has
been reported to inhibit TNF-induced IL-1𝛽, MMP-3 release and
expression in human RA-FLS via modulation of the PI3kinase/Akt
pathway.28 In experimental inflammatory arthritis models it has
shown to suppress Th17 cell expansion and pro-inflammatory
signature cytokine produced by these cells.29 As Th17 cells play
a critical role for tissue damage in synovial joints of patients with
RA, cellular modulations for the Th17-cell-polarised responses by
resveratrol could improve the outcome of RA patients.30

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Table 3. Main polyphenolic compounds investigated in crystal-induced arthritis and their effects demonstrated in the different cellular or animal
model

Polyphenol Model Actions

Ferulic acid Rat model ↓Oedema, proteolytic enzymes, CK, oxidative stress, inflammasome, transcriptional
factors
↑ Antioxidant enzymes
Clorogenic acid Mouse model ↓ Uric acid
Rat model ↓ Xanthine oxidase, swelling, CK, transcriptional factors
Quercetin Rat model ↓ Oedema, leucocyte recruitment, CK, PG, oxidative stress
↑ Antioxidant enzyme
Human ↓ Uric acid
Pycnogenol Chondrocytes Synoviocytes ↓ Oxidative stress, CK, COX-2, transcriptional factors
Rat model ↓ CK, oxidative stress
Morin Macrophage cells ↓ CK, oxidative stress, prostaglandins, lysosomal enzymes, transcriptional factors
Rat model ↓ Swelling, leucocyte infiltration, oxidative stress, inflammasome, CK, COX-2,
proteolytic enzymes, transcriptional factor
↑Antioxidant enzymes
Resveratrol Mouse model ↓ Swelling, uric acid, CK
Mononuclear cells Macrophage cells ↓ CK, phosphorylation of cap-dependent translation inhibitor
↓ Inflammasome activation, mitochondrial damage
Mouse model ↓ CK, recruitment of neutrophils, inflammasome activation
Catechin Mouse model ↓ CK
Mononuclear cells ↓ CK, inflammasome activation, oxidative stress
EGCG Mouse model ↓ Neutrophil infiltration, CK, inflammasome activation

PG, prostaglandins; CK, cytokines; ROS, reactive oxygen species; COX, cyclooxygenase.

Recently, rats with adjuvant-induced arthritis treated
with resveratrol showed a decreased serum levels of spe-
cific RA biomarkers [rheumatoid factor, MMP-3, cartilage
oligomeric matrix protein, IgG, antinuclear antibody (ANA),
TNF, myeloperoxidase, C-reactive protein (CRP) and malondi-
aldehyde], and increased those of IL-10 and glutathione, known
anti-inflammatory mediators.31 This aspect is important as serum
levels of MMPs and collagen biomarkers are known to correlate
with disease activity.32
Oral administration of EVOO polyphenol extract has been shown
to reduce joint oedema, migration of inflammatory cells, cartilage
alterations and bone erosion in the model of CIA in mice. The
mechanisms linked to these effects has been related to the inhibi-
tion of c-Jun N-terminal kinase (JNK), p38, STAT3 and NF-𝜅B factors
which, in turn, regulate the production of inflammatory mediators
such as IL-1𝛽, TNF, IL-6 and PGE2.33 Different studies indicate that
HT represents one of the main EVOO components responsible for
these beneficial effects.
Using the same animal model, some investigators demonstrated
that genistein, a soybean-derived polyphenol, induced a decrease
in serum levels of autoantibodies to collagen II and the secretion
of interferon gamma (IFN-𝛾), a cytokine abundantly expressed in
rheumatoid synovitis.34
Suppression of proteases and other cytokines has been obtained
in in vitro studies after stimulation of RA-FLS with TNF𝛼, one of the
most important mediator of the disease.35,36
Interesting results with regard to the regulation of inflam-
mation and bone destruction have been observed in RA as
far as tea polyphenolic components are concerned. In particu-
lar, the green tea active constituent EGCG has been shown to
down-regulate chemokine and proteolytic enzyme production
in IL-1𝛽-stimulated RA-FLS and inhibit the phosphorylation of
important kinases and the activation of NF-𝜅B.37 Moreover, the
treatment of RA synoviocytes with EGCG decreased TNF-induced
expression and release of MMP-1 and MMP-3, and phosphoryla-
tion of MAPK.38
The effect of EGCG has been also evaluated on disease devel-
opment and severity using a mouse model of RA. Reduced histo-
logical scores and improvement of clinical symptoms have been
obtained in mice treated with EGCG and the mechanism of action
has been linked to the activation of antioxidant pathways.39,40
Intra-articular injection of EGCG has also been tested in animal
models of CIA and showed interesting prophylactic and therapeu-
tic properties.41
Similar results in terms of anti-inflammatory and antioxidant
effects have been obtained with another polyphenol commonly
present in green tea, kaempferol.42
Anti-inflammatory effects have been demonstrated with regard
to emodin, a polyphenolic compound mainly obtained from
rhubarb. Emodin has been demonstrated to exert a protec-
tive action in hypoxic rheumatoid synoviocytes by inactivating
enzymes involved in epigenetic mechanisms, such as histone
deacetylase, and reducing the production of pro-inflammatory
mediators.43 In another study, it has been shown to inhibit osteo-
clast differentiation, and classical inflammatory pathways in CIA
mice.44
Similar anti-inflammatory activities were observed in in vitro
and in vivo models investigating the effect of many additional
polyphenolic compounds, such as mangiferin, cocoa extracts,
thymoquinone, hesperidin, malvidin-3-O-𝛽, gallic acid.19
Overall, the potential benefit exerted by polyphenols in RA has
been demonstrated in different pro-inflammatory pathways that
are dysregulated and lead to joint destruction in RA.
POLYPHENOLS IN CRYSTAL-INDUCED
ARTHRITIS
Crystal-induced arthritis encompasses gout and calcium
crystal-related arthritis. These diseases are caused by the

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Polyphenols in arthritis
deposition of, respectively, monosodium urate (MSU) and cal-
cium pyrophosphate (CPP) crystals in articular or periarticular
tissues. These crystals provoke an acute, intense inflammatory
reaction characterised by massive leucocyte recruitment and the
local release of cytokines, chemokines, reactive oxygen species
and proteolytic enzymes.45
IL-1𝛽 represents the most important inflammatory media-
tor in crystal-induced inflammation and its release depends
on the activation of the NACHT-LRRPYD-containing protein-3
(NLRP-3) inflammasome in mononuclear cells. Since the time
this pathway was first identified, IL-1𝛽 has been considered one
of the most important pharmacological targets in gout and cal-
cium crystal-induced arthritis.46 IL-1𝛽 RNA expression, however,
depends on signals leading to the activation of the transcrip-
tional factor NF-𝜅B (e.g. different proteins, TLR2 ligands, uric
acid). Several pathways can be therefore considered when the
anti-inflammatory role of natural substances is investigated in
crystal-induced arthritis.
Polyphenols have been shown to act whether by decreasing
uric acid levels, the main risk factor for gout development, or the
inflammatory response to pathogenic crystals described above
(Table 3).
Chlorogenic acid, a phenolic compound identified in differ-
ent foods, including peach, eggplants and green tea, has been
shown to reduce uric acid levels by inhibiting the activity of xan-
thine oxidase in a model of induced hyperuricaemia in mice.47 A
down-regulation of the activity of the transcriptional factor NF-𝜅B,
COX-2 and caspase-3, along with a decreased production of the
inflammatory mediators IL-1𝛽, TNF and IL-6 have been observed
in the same study using a model of MSU crystal-induced inflam-
mation in rats.47
Similar results have been obtained by using ferulic acid, a ubiqui-
tous plant polyphenol, which also demonstrated inhibition of the
NLRP3 inflammasome and an increase in the antioxidant enzymes
superoxide dismutase (SOD) and catalases.48
Arthritis induced by intra-articular injection of MSU crystals
inside the ankle joint of the rat represents a model largely used
to study the effect of various substances in gout. In this model
quercetin has been shown to reduce oedema and histological
inflammatory signs along with the levels of pro-inflammatory
chemokines, lipid peroxidation and an increase in antioxidant
enzyme activity.49 Quercetin, which is ubiquitous in plant
food sources and a major bioflavonoid in the human diet, has
recently demonstrated important beneficial effects in lowering
plasma concentrations of uric acid in a randomised-controlled
trial.50
The inhibition of the experimental MSU crystal-induced arthritis
has been obtained by the polyphenolic compounds pycnogenol,
morin and p-coumaric acid which, in addition, exhibited analgesic
and antipyretic effects.51 – 53 Morin has been shown to exert its
anti-inflammatory effects in macrophages mainly through the
inhibition of COX-2 protein expression and the inactivation of
NF-𝜅B signalling pathway.54
Among polyphenols, resveratrol (RES) has received a great deal
of attention in different chronic inflammatory conditions includ-
ing crystal-induced arthritis. RES has been demonstrated to sup-
press inflammation in both in vivo and in vitro experiments and
to reduce serum uric acid levels.55 The mechanism of action of
RES involved, in particular, the suppression of the activation of the
NLRP3-inflammasome which, as stated above, leads to the produc-
tion of IL-1𝛽.56 RES has been shown to prevent the accumulation of
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acetylated 𝛼-tubulin and thus inhibits the assembly of the NLRP3
inflammasome in macrophages.56
EGCG and other catechins have been shown to ameliorate
MSU-induced inflammation affecting IL-1 production and the
NLRP3 pathway.57
While many polyphenolic compounds have demonstrated a
potential therapeutic effect in gout, fewer studies are available
as far as calcium crystal-related arthritis is concerned. One of our
previous studies demonstrated that EGCG is effective in reducing
pro-inflammatory cytokines and chemokines in FLS and mono-
cytes stimulated with CPP crystals. The inhibition of the migration
of neutrophils and mononuclear cells has also been observed in
the presence of this polyphenol.9
In summary, polyphenols in crystal-induced arthritis seems to
have a dual role. They act on uric acid levels by decreasing
the activity of xantine oxidase and having, in parallel, a gen-
eral anti-inflammatory effect. The latter involves the inhibition of,
firstly, the NF-𝜅B signalling pathway which leads to IL-1 transcrip-
tion and, secondly, inflammasome activation which allows the
release of IL-1 into the extracellular space.
POLYPHENOLS IN OTHER RHEUMATIC
DISEASES
A few studies have investigated the role of polyphenols in other
rheumatic diseases, such as SLE and fibromyalgia. The first is
an autoimmune chronic disease that causes systemic inflamma-
tion and affects multiple organs. Although clear inflammatory
signs and, in particular, the acute phase response are frequently
lacking in most patients affected by SLE, increased levels of
pro-inflammatory cytokines have been found in the serum of these
patients. In this disease, polyphenolic compounds can have bene-
ficial effects inhibiting, for instance, the transcription and transla-
tion of autoantigens which cause inflammation and inflammatory
injuries such as skin lesions.58
Some polyphenols have been studied with regard to their
effect in gut microbial dysbiosis that has also been related to
the initiation and amplification of SLE, and more generally to
the modulation of both immune and inflammatory processes in
chronic conditions.59 A study has identified a positive association
between polyphenol intake, mainly flavones and flavanones from
oranges, apples and red wine, and specific beneficial intestinal
bacterial populations, such as Lactobacillus, Bifidobacterium and
Faecalibacterium.60
More recently, an EVOO diet has demonstrated attenuation of
renal injury in the pristane-induced SLE model via activation of
the HO-1/Nrf-2 antioxidant pathway and suppression of JAK/STAT,
NF-𝜅B and MAPK activation. In addition, SLE mice treated with
EVOO showed a reduction in MMP-3 serum and PGE2 kidney levels
as well as a decrease LPS-induced production of TNF, IL-6, IL-10 and
IL-17 in splenocytes.61
As far as fibromyalgia is concerned, this disease is characterised
by chronic widespread pain and increased pain sensitivity, often
accompanied by several concomitant symptoms. An increase in
serum inflammatory mediators can be observed during the active
phase of the disease. Studies on patients consuming an antioxi-
dant diet reported a decrease in their joint stiffness and pain as
well as an improvement of their self-experienced health. In those
studies, the intake of polyphenol-rich foods has been shown to
be associated with a lower number of tender points, although by
unknown mechanisms.62
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CONCLUSIONS
The results of the studies outlined in this review show how
plant-derived polyphenols can have an important role in
contrasting the inflammatory process that characterises arthritis
and leads to joint destruction.
Interestingly, single polyphenolic compounds have been shown
to affect different inflammatory pathways and cell type (e.g. chon-
drocytes, FLSs, monocytes, lymphocytes) response in different
arthropathies. This is a relevant aspect in diseases which often
present an over-expression of multiple inflammatory mediators
such as proteases, cytokines, chemokines and oxidant products.
One of the most important aspects focussed upon in this review
is the potential preventive role of polyphenols on articular dam-
age. This effect may be exerted through the inhibition of signal
transduction pathway activation, which involves kinases and tran-
scriptional factors, and also by the inhibition of the production of
autoantibodies and autoantigens which lead to the development
of some rheumatic diseases such as SLE and RA. Thus, polyphenols
may be included in the limited list of substances considered able
to reduce the possibility that a state of pre-serological disease can
evolve into an overt disease.
Currently, effective therapies are available for most of the
arthropathies, thanks, in particular, to the new biological drugs.
However, it is still not possible to arrest the degenerative process
in OA, where the best intervention consists in the reduction of risk
factors which favour the disease onset. In this context polyphenols
can play an important role in both improving the inflammatory
reactions and reducing the degenerative process occurring in OA.
Finally, the beneficial cellular effects demonstrated in in vitro
studies need to be proved in a large group of patients. The
development of clinical interventional trials could represent the
basis to establish dietary recommendations in patients affected
with rheumatic diseases.
ACKNOWLEDGEMENT
This work was supported by institutional research grants
(DOR1658992/16, DOR60A079132/15) from the University of
Padova.
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