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Prostaglandins, Leukotrienes and Essential Fatty Acids 82 (2010) 315–318
Contents lists available at ScienceDirect
Prostaglandins, Leukotrienes and
Essential Fatty Acids
journal homepage: www.elsevier.com/locate/plefa
Dietary fatty acids and arthritis
S. Hurst 1, Z. Zainal 2, B. Caterson, C.E. Hughes, J.L. Harwood n
School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK
a r t i c l e in fo
Keywords:
Omega-3 polyunsaturated fatty acids
Dietary lipids
Osteoarthritis
Rheumatoid arthritis
Eicosapentaenoic acid
Docosahexaenoic acid
abstract
Musculoskeletal complaints are the second most frequent reason for medical treatments. Within these
diseases rheumatoid arthritis (RA) and, especially, osteoarthritis (OA) are common. Although the causes
of arthritis are multifactorial and not fully understood, clinical trials have generally shown benefit from
dietary n-3 polyunsaturated fatty acids. This has usually been attributed to their anti-inflammatory
properties. Recently we have used in vitro model systems to study the molecular mechanism(s) by
which n-3 PUFAs may act to alleviate the symptoms of arthritis. These experiments showed that n-3
PUFAs reduce expression of cartilage-degrading proteinases, cyclooxygenase-2 and inflammatory
cytokines. Eicosapentaenoic acid (EPA) was more effective than docosahexaenoic acid (DHA) or alphalinolenic acid. The data provide a scientific rationale for the consumption of n-3 fatty acids as part of a
healthy diet and perhaps in treating arthritis.
& 2010 Elsevier Ltd. All rights reserved.
1. Arthritis is a common complaint
Musculoskeletal complaints are the second most frequent
reason for going to a doctor and represent 10–20% of primary care
consultations [1]. Within these diseases, arthritis and rheumatism
are prominent. Rheumatoid arthritis (RA) is a chronic, systemic,
inflammatory, autoimmune disorder which is not well understood and which requires precise matching to specific criteria in
order to be diagnosed initially (see [2]). Major characteristics are
listed in Table 1.
The most common articular disorder is osteoarthritis (OA) and
this accounts for more disability in the elderly than any other
disease [3]. It is a slowly progressing chronic disease which
is characterised by loss of articular cartilage within synovial
joints. Typical clinical manifestations are joint pain, restriction
of movement and local inflammation [2]. A summary of major
characteristics is given in Table 2.
An indication of the prevalence (and associated costs
of arthritis—OA and RA mainly) is shown in Table 3. Partly
because there is a lack of regular data collection, the incidence of
OA and RA is difficult to estimate and reports of the prevalence
vary somewhat [2]. OA is much more common than RA, which
in turn affects women more than men. In the UK, incidence of
RA (in 2001) has been estimated as 1.16% for women and 0.44%
n
Corresponding author.
E-mail address: [email protected] (J.L. Harwood).
1
Current address: School of Medicine, Cardiff University, Cardiff CF14 4XN,
Wales, UK.
2
Current address: Malaysian Palm Oil Board, Persairan Institusi, 4300 Kajang,
Selangor, Malaysia.
0952-3278/$ - see front matter & 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.plefa.2010.02.008
for men [4]. For OA worldwide, the incidence is 9.6% for men and
18.0% for women aged 60 years and over [1]. Overall in the USA,
30% of the population have symptoms of arthritis (2/3rds of
whom need medication), 5–10% have disability which is related to
the disease and 0.5% are totally disabled as a result of the disease
[3]. Similar figures apply to the UK [2]. While the prevalence and
severity of OA and RA increase inexorably with age [1], there is
some evidence that the absolute incidence of RA is reducing,
particularly in women. The reason(s) for this is unclear but
may be due to environmental factors, a protective effect from
oral contraceptive pills and/or a general reduction in bacterial
infections [2].
Although limited mortality is attributed to arthritis, the
diseases cause intense suffering. Joint stiffness and pain are the
usual symptoms and the morbidity associated with arthritis has a
massive economic cost (see Table 3). For the UK approaching a
quarter of the total working days lost through illness were due
to arthritis, costing about £18 billion in 2000 [2]. However one
looks at it – prevalence, economic cost, suffering – arthritis is a
huge problem.
2. Risk factors for arthritis
OA and RA have multiple risk factors which, to a large extent,
overlap. These are discussed well by Rayman and Callagher [2].
Genetic factors have been implicated in both the susceptibility
and severity of RA while they play a major role for the incidence
of OA in different tissues (e.g. 60% in hip, 70% in spine). As
mentioned before, age is a major factor with OA starting to
increase markedly beyond age 50 and RA increasing after 40 in
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Table 1
Major characteristics of rheumatoid arthritis.
Chronic, systemic, inflammatory autoimmune disorder
Usually begins in small joints of the hands and feet
Spreads to larger joints
Inflamed joint lining extends and erodes articular cartilage and bone
Joint deformity
Progressive physical disability
Table 2
Major characteristics of osteoarthritis.
Most common articular disorder
Accounts for more disability amongst elderly than any other disease
Affects hands or weight bearing joints (hips, knees, spine)
Slowly progressing chronic disease
Loss of articular cartilage
Joint pain, tenderness, limitation of movement
Local inflammation
Table 3
The incidence, morbidity and economic costs of arthritis.
In USA, 30% of the population have some symptoms of arthritis
RA more prevalent in women
RA affects 0.3–1% of population in USA and Europe
In UK, OA affects 7–13 million
10% World’s population 460 years of age have symptomatic problems
Quality of life severely impaired
206 million working days lost annually in the UK (46 million due to RA)
In UK, £1.1 billion annual expenditure on prescribed medications and
operations
both men and women. While sports injuries and trauma are
associated with OA, obesity increases the risk of both RA and OA,
while smoking (associated with the production of rheumatoid
factor) is a significant risk factor for RA.
Inconsistent and often conflicting evidence for different dietary constituents as risk factors for OA and RA have been found [2].
These include coffee, tea and alcohol. On the other hand, positive
benefits have been associated with vitamin C and, especially,
vitamin D. For dietary fats, lower incidences of RA were found in
various studies for olive oil and fish consumption. The beneficial
effect of fish was related to its n-3 polyunsaturated fatty acid
(PUFA) content [2].
3. Clinical evidence for a benefit of dietary n-3 PUFAs
Our awareness of the potential benefits of n-3 PUFAs for
arthritis are long standing. In 1783 Percival [5] wrote that cod
liver oil should be given in ‘‘obstinate chronic rheumatisms,
sciaticas of long standing and in those cases of premature
decrepitude’’. Much more recently, further interest in fish oils
containing n-3 PUFAs derived from the observations that the
Inuits and the Japanese (who have an increased level of a high
susceptibility gene for RA) [6,7] both have low incidence of
arthritis.
The subject of the importance of dietary PUFAs in the
treatment of arthritis has been excellently covered by Rayman
Table 4
Some clinical studies on the efficacy of dietary n-3 PUFAs.
Parameter
Reference
[13] [14] [15] [16] [17] [18] [19] [20] [21] [22]
Morning stiffness +
Onset of fatigue
+
Grip strength
+
Walk time
NE
Tender joints
++
Swollen joints
NSAID reduction
Pain
NE
++
NE
NE
++
+
+
++
NE
++
++
+
++
+
NE
++
+
NE
+
NE
NE
NE
+
NE
+
+
NE
+
+
+
+
++
NE
NE, no effect; + reduced; ++ strongly reduced.
and Callaghan [2] and we will only make summary observations
here.
Almost all of the clinical studies have focussed on RA, which is
a pity since OA is much more prevalent. There have been around
20 studies of the use of fish oil (and (oily) fish) intake on RA. For
most of these studies improvement in at least two clinical
outcomes was achieved (see Table 4 for a summary of some
trials). Apart from subjective assessments by patients (e.g. grip
strength, stiffness, joint pain), intake of non-steroidal antiinflammatory drugs (NSAIDs) and biochemical measurements of
inflammation (e.g. interleukin-1, leukotriene B4) were amongst
the outcomes included in some studies. Dietary fish oil intakes
and RA have been reviewed [8–11]. Because not all n-3 PUFAs
are equally effective [12], due in part to metabolic restrictions
(which will be commented on later), there has been a focus on
the content of n-3 eicosapentaenoic acid (EPA) and n-3
docosahexaenoic acid (DHA) in evaluating clinical effectiveness.
For the studies summarised above the doses of EPA and DHA were
in the range 1–7 g/day. This variability in experimental design is
compounded by different durations of supplementation,
ignorance of other confounding dietary constituents (e.g. n-6
PUFAs), lack of recognition of genetic variation, as well as a
frequent lack of plasma measurements to estimate both the level
of compliance and incorporation of the assumed biologically
active fatty acids.
Meta-analyses of the trial data have been carried out. Fortin
et al. [23] included trials that were double-blind, placebocontrolled and showed randomisation as well as parallel or
crossover design. They examined data from seven published trials
and included additional data from a further three unpublished
trials. Improvements in morning stiffness and tender joints were
statistically significant, but not other outcomes such as grip
strength or joint swelling. MacLean et al. [24] examined 21
studies that met US Department of Health and Human Services
inclusion criteria. From these they used 5–9 sets of data for four
outcomes (pain, joint swelling, disease activity and overall patient
assessment). Improvement was found for all four evaluations on
fish oil treatment but none reached statistical significance. The
use of NSAIDs in 4 of the above studies was also assessed. Fish oil
lowered NSAID use significantly in 3 of these [24]. In another
study measuring the effect of fish oil alone or with olive oil, the
latter combination proved more effective – perhaps because olive
oil is thought to decrease expression of intercellular adhesion
molecule-1 and, also may increase incorporation of n-3 PUFAs
into membranes [25]. Moreover, oleic acid (which is highly
enriched in olive oil) can be metabolised to n-9 eicosatreienoic
acid and this can, in turn, reduce the production of the proinflammatory leukotriene B4 from arachidonic acid [25,26].
The modest effects seen for dietary fish oils in many trials may
have an explanation in ‘biological variation’. In particular, genetic
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Table 5
Possible limitations of human intervention trials on arthritis with n-3 PUFAs.
Too short a duration
Inappropriate (inflammatory or anti-inflammatory) placebo used
Dose of n-3 PUFAs too low
Inappropriate n-3 PUFAs used (18 carbon fatty acids much less effective)
Other dietary components (e.g. n-6 PUFAs) not considered
Patient genotype and medication can confound results
Based on [2].
differences may make some individuals more responsive to n-3
PUFAs because of their inherent inflammatory cytokine production [27,28]. Moreover, as pointed out before (and discussed in
[2]), other components in the diet can influence the effectiveness
of the n-3 PUFAs. Thus, although specific n-6 PUFAs, namely glinolenic acid(GLA; 18:3n-6) and dihomo-g-linolenic acid (DGLA;
20:3n-6) may help alleviate some symptoms of RA (see [9]), it is
usually thought that dietary n-6 PUFAs are pro-inflammatory and
will, therefore, reduce the effectiveness of EPA and DHA or fish
oils. Thus, there have been some trials where the intake of n-6
PUFAs was deliberately restricted. These tended to show an
enhanced benefit for the dietary n-3 PUFAs [29–31].
Because clinical trials have been conducted over the last 20
years and our knowledge of the biochemistry and mechanisms of
action of n-3 PUFAs has evolved over that period, limitations are
clearly present for the evaluation of the data. These limitations are
summarised in Table 5 and are discussed in [2]. In particular,
inappropriate placebos have often been chosen and this is a
problem with many animal studies using n-3 PUFAs also.
So far as current intakes of n-3 PUFAs are concerned, most
European and North American populations consume considerably
less than the current dietary recommendations for n-3 PUFAs
(about 0.5 g/day of EPA plus DHA) let alone the higher levels
associated with demonstrable anti-inflammatory effects [2].
Moreover, the dietary ratio of n-6:n-3 PUFAs may be important
(see [12]), and typical Western diets currently have a ratio of
10–15 where a ‘healthier’ ratio is thought generally to be in the
range 3–4.
4. Probing the molecular mechanism by which n-3 PUFAs can
be of benefit for arthritis
The way in which dietary n-3 PUFAs can be of benefit in
arthritis is not entirely clear. Nevertheless, based on evidence
from clinical studies as well as our knowledge of the metabolism
and molecular effects of n-3 PUFAs, we can summarise these as
being to lower inflammation and to reduce cartilage destruction.
To do this n-3 PUFAs may have some specific actions which vary
in extent according to individual cellular/tissue conditions,
genetic predisposition and environmental (including diet-derived) factors. These are listed in Table 6.
In order to define the molecular mechanisms more fully we
have used in vitro culture systems that mimic many of the
degenerative features and inflammatory pathways involved in
arthritis [32,33]. These culture systems used chondrocytes or
cartilage explants derived from bovine metacarpo- or metatarsophalangeal joints (7-day-old calves) or from human patients
undergoing total knee replacement surgery for OA. The bovine
systems were stimulated with interleukin-Ia and the human
tissues with interleukin-1b to elicitate an inflammatory response.
We then evaluated mRNA levels for proteinases, COX-1 and -2,
lipoxygenases and inflammatory cytokines as well as protein
levels and activities of some of the above. By using these in vitro
317
Table 6
Molecular mechanisms by which n-3 PUFAs may act to reduce symptoms of
arthritis.
Compete with n-6 PUFAs in metabolism to eicosanoids
Produce less (non-) inflammatory eicosanoids
Produce anti-inflammatory resolvins, docosatrienes, etc.
N-3 PUFA derived eicosanoids compete with n-6-derived compounds for
receptors
Reduce gene expression of cyclooxygenase-2 (COX-2) but not COX-1
Reduce gene expression of inflammatory cytokines
Reduce gene expression of cartilage-degrading proteinases
Affect signalling pathways for transcription factors (e.g. NFkB)
Reduce lymphocyte proliferation
Table 7
Summary of the effects of the in vitro action of n-3 PUFAs on factors associated
with arthritis pathology.
Factor
Effects
Comments
ADAMTS-4
mRNA levels reduced by n-3
PUFAs
As above but EPA much more
effective
Cause the initial
proteolysis of
cartilage
MMP-3
EPA reduced mRNA levels
MMP-13
As above
Responsible for further
protein degradation.
Elevated in arthritis
COX-1
No effect of any n-3 PUFA
The constitutive
isoform
COX-2
mRNA, protein, activity
reduced by n-3 PUFAs
Inflammation-induced
isoform
IL-Ia
IL-Ib
Induced by inflammation and
reduced by n-3 PUFAs (but not
by n-6 PUFAs) with
EPA4 DHA4ALA
IL-I and TNF-a are the
main cytokines
associated
with the inflammation
in arthritis
ADAMTS-5
TNF-a
The experimental results are shown in Refs. [34–36]. Abbreviations: MMP, matrix
metalloproteinase; COX, cyclooxygenase; IL-I, interleukin-I; TNF, tumour nucrosis
factor; ALA, alpha-linolenic acid; ADAMTS, A Disintegrin And Metalloproteinase
with ThromboSponin motifs (ADAMTS-4 and -5 were previously called aggrecanase-1 and -2, respectively).
model systems, we were able to test directly various PUFAs
(including different n-6 and n-3 PUFAs) for their ability to change
expression and/or activity of factors associated with the pathology of arthritis. The overall results are summarised in Table 7.
In a series of experiments we tested the relative efficacy of
three n-3 PUFAs (a-linolenic acid, EPA, DHA). Overall, the n-3
PUFAs reduced mRNA levels for the key initial cartilage-degrading
proteinases ADAMTS-4 and -5 and the matrix metalloproteinases
(MMP)-3 and -13, which are all known to be important in
arthritis. They also reduced mRNA for COX-2 (but not the
constitutive COX-1) and for the inflammatory cytokines, tumour
necrosis factor-a (TNF- a), interleukin-1a (IL-1a) and interleukin1b (IL-1b) [34]. EPA was the most effective of the three n-3 PUFAs
tested [34].
We also showed that it was possible to modify palm oil
(the world’s major edible oil) by esterification with EPA to
produce a product that had effective anti-inflammatory properties. The EPA-enriched oil (but not the un-modified palm oil)
reduced the IL-1-induced expression of ADAMTS-4, COX-2, TNF-a,
IL-1a and IL-1b in a concentration-dependent manner back down
to control (un-induced) levels [35].
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Because COX-2 is a key enzyme for inflammatory responses,
we examined its expression and activity in more detail. Using
both bovine and human culture systems, we showed that EPA was
able to reduce COX-2 mRNA and protein levels. Activity (assessed
by prostaglandin E2 production) was reduced in a concentrationdependent manner by EPA. These effects of EPA contrasted with
those of arachidonic acid, which did not alter COX-2 expression or
activity [36]. These data provide direct evidence that beneficial
effects of dietary n-3 PUFAs (particularly EPA) can involve
reduction in the expression and, hence, activity of the key COX2 enzyme.
Further exploitation of these in vitro model systems should be
able to elucidate additional molecular mechanisms of relevance to
the progression of arthritis. Such mechanisms could include the
role of transcription factors as well as cross-talk between different
signalling pathways. Furthermore, they may also provide information concerning the competition between different individual PUFAs which may influence dietary advice for ‘healthy’ as
well as arthritic patients.
Acknowledgements
The author’s research in this field has been supported
financially by the Arthritis Research Campaign, the Biotechnology
and Biological Sciences Research Council and the Malaysian Palm
Oil Board.
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