- ADAMTS
-
a disintegrin and metalloproteinase domain with thrombospondin motifs
- ASU
-
avocado-soyabean unsaponifiables
- COX
-
cyclooxygenase
- Gla
-
γ-carboxyglutamic acid
- MMP
-
matrix metalloproteinase
- OA
-
osteoarthritis
Osteoarthritis (OA) is a degenerative joint disease characterised by degradation of articular cartilage, thickening of subchondral bone and osteophyte formation. Incidence and prevalence of OA has been difficult to assess, in part because of heterogeneity in definitions of the disease. A recent meta-analysis suggested that overall prevalence of OA at different anatomical sites was 23·9 % (knee), 10·9 % (hip) and 43·3 % (hand), although only the prevalence of knee OA showed a gender difference between women and men (27·3 and 21 %, respectively)( Reference Pereira, Peleteiro and Araujo 1 ).
Osteoarthritis is a leading cause of disability in the UK. A recent survey( 2 ) found 8·5 million people in the UK with OA, with 71 % of these in constant pain. There are no effective disease-modifying drugs to treat OA and drugs that relieve pain are often insufficient. Joint replacement is offered to patients at end-stage disease with 66 436 hip and 77 578 knee replacements due to OA performed in the UK in 2011( 3 ).
Two major risk factors for OA are increasing age (most affected patients are aged >45 years and the greatest morbidity is seen in patients aged >60 years)( Reference Shane Anderson and Loeser 4 ) and increasing obesity( Reference Richmond, Fukuchi and Ezzat 5 ). With changing demographics, OA is an increasing public health and economic burden. The economic costs of OA in the UK are largely unknown, but direct costs have been estimated at approximately £1 billion/year. With inclusion of indirect costs, estimates from the USA range up to £8 billion/year( Reference Chen, Gupte and Akhtar 6 ).
Although the ability to slow or stop the progression of OA would have individual and population-level benefits, few pharmaceutical companies maintain OA as a disease area. This is in part because there is no precedent. Furthermore, OA generally progresses slowly, and there are no current validated biomarkers for cartilage destruction (joint space narrowing, assessed on X-ray, is the only Food and Drug Administration approved end point in a clinical trial)( Reference Kraus 7 ). Issues of toxicity, in a disease that is not life-threatening, can also make drug development problematic. It is possible to overcome at least some of these issues by selection of the patient group (where particular sub-groups are known to progress more rapidly), and by establishing the dose of drug that gives efficacy within the target tissue (i.e. cartilage)( Reference Jordan, Sowers and Messier 8 ).
Focusing on compounds from the habitual diet that may prevent the onset or slow the progression of OA is an alternative strategy. Since in essence, all of the population can be viewed as at risk for the development of OA in old age, an approach that relies on dietary modification is clearly more attractive in terms of risk/benefit and more likely to be implementable. However, detailed molecular studies ahead of a full clinical trial are required in order to design trials optimally that will examine potential efficacy.
There are currently limited data on the inter-relationship between diet and OA. Data come from a variety of studies: in vitro cell and tissue explant models, animal models, epidemiological associations and intervention trials. There is a large variability between studies, e.g. in animal models, a dietary intake approach would be optimal in order to relate to human exposure, but some studies use intra-articular injection and/or concentrations not achievable through the diet. The intervention trials conducted to date have many different designs, number of patients, time length and outcome measures, often with too few patients and of short duration. There is a need for better quality data before dietary advice can be given. However, clinical trials in OA are expensive and it is not clear who will or should fund them.
This brief review focuses predominantly on potential dietary factors than may reduce the risk or progression of the disease. It focuses only on OA, mainly ignoring data coming from more overtly inflammatory arthritides.
Two pertinent ‘nutraceuticals’ will not be discussed, but should be mentioned: glucosamine and chondroitin. Glucosamine is a sugar and precursor for glycosaminoglycan and therefore proteoglycan biosynthesis. Chondroitin is a glycosaminoglycan, a form of which is found in aggrecan, the major proteoglycan in cartilage. Hydrochloride and sulphate salts of both glucosamine and chondroitin have been extensively examined in laboratory models and clinical trials. The efficacy of these compounds remains controversial, but most recent analyses appear to indicate that high-grade preparations of chondroitin sulphate and glucosamine sulphate, may have efficacy in OA( Reference Black, Clar and Henderson 9 – Reference Wu, Huang and Gu 13 ).
Micronutrients
Vitamin C
In prospective studies examining micronutrient intakes, the Framingham study identified a protective association between higher intake of vitamin C and the progression of radiographic knee OA( Reference McAlindon, Jacques and Zhang 14 ) and a higher vitamin C intake was also associated with lower risk of knee pain( Reference McAlindon, Jacques and Zhang 14 , Reference McAlindon 15 ). However, a longitudinal study showed no protective effect of vitamin C supplements on the progression of knee OA, although in multivariate analyses vitamin C supplements were beneficial in preventing the development of knee OA( Reference Peregoy and Wilder 16 ). In healthy subjects, vitamin C intake has been associated with reduced risk of bone marrow lesions on MRI( Reference Wang, Hodge and Wluka 17 ). In these publications, vitamin C has been viewed simply as an antioxidant, but it should not be forgotten that vitamin C is a co-factor enabling the proline and lysine hydroxylation essential for correct collagen biosynthesis. It also has effects on regulating the expression and translation of collagen, a major component of many connective tissues including cartilage and bone( Reference Clark, Rohrbaugh and Otterness 18 ). Animal model data (all from the guinea pig) are conflicting. Early studies showed that dietary ascorbate decreased pathology in surgically induced OA( Reference Schwartz, Oh and Leveille 19 ). In a further study, additional ascorbate in the drinking water showed a protective effect on spontaneous cartilage lesions, but no effect on pathology post-surgery( Reference Meacock, Bodmer and Billingham 20 ). Most recently, ascorbate supplementation increased disease severity in spontaneous OA( Reference Kraus, Huebner and Stabler 21 ).
Vitamin E
The Framingham study identified a weak protective association between higher intake of vitamin E and the progression of radiographic knee OA( Reference McAlindon, Jacques and Zhang 14 ). A study examining tocopherol isoforms and radiographic knee OA suggested complex associations( Reference Jordan, De Roos and Renner 22 ) and intervention trials of vitamin E have to date been contradictory( Reference Canter, Wider and Ernst 23 ). In vitro data in chondrocytes are sparse, but a recent study suggests that vitamin E protects against hydrogen peroxide-induced changes in extracellular matrix gene expression( Reference Bhatti, Mehmood and Wajid 24 ).
Vitamin D
Vitamin D has multiple functions in the musculoskeletal system, particularly in bone health and pathologies( Reference Wolff, Jones and Hansen 25 ). Many studies have explored the association between vitamin D levels and OA. Recent systematic review suggests that low serum concentrations of 25-hydroxyvitamin D are associated with increased radiographic progression of OA, but associations are weaker with symptoms of disease( Reference Cao, Winzenberg and Nguo 26 ). A recent longitudinal study demonstrated the converse, that moderate vitamin D deficiency predicts both knee and hip pain, independent of structural change( Reference Laslett, Quinn and Burgess 27 ). However, a recent 2-year intervention trial showed no decrease in knee pain or structural change in patients with knee OA, with knee function significantly worse following vitamin D intervention( Reference McAlindon, LaValley and Schneider 28 ). Further intervention trials are ongoing( Reference Cao, Jones and Cicuttini 29 ). Vitamin D supplementation in a rat post-surgical model of OA showed a protective effect during the early phase of the disease, but not during the later phase( Reference Castillo, Hernandez-Cueto and Vega-Lopez 30 ). However, this was scored using condyle width, an unusual method. Interestingly vitamin D receptor-deficient mice showed aggravated inflammation and cartilage damage when crossed into a TNF transgenic model( Reference Zwerina, Baum and Axmann 31 ).
Other micronutrients
In a Japanese population (Research on Osteoarthritis Against Disability), low habitual vitamin K intake was the only dietary factor associated with the increased prevalence of radiographic knee OA in a cross-sectional study( Reference Oka, Akune and Muraki 32 ). This supports data from US cohorts where low vitamin K was associated with OA in the hand and knee( Reference Misra, Booth and Tolstykh 33 , Reference Neogi, Booth and Zhang 34 ). However, a further study, using minimum joint space width and osteophytosis as variables showed an association of vitamins K, B1, B2, B6 and C with the former and vitamins E, K, B1, B2, niacin (B3) and B6 with the latter, both in women only( Reference Muraki, Akune and En-Yo 35 ). Vitamin K is an essential co-factor for the formation of γ-carboxyglutamic acid (Gla) residues, and Gla-containing proteins include osteocalcin and matrix Gla protein, both expressed in the skeleton. Vitamin K regulates mineralisation in both bone and cartilage( Reference Krueger, Westenfeld and Schurgers 36 ). Polymorphisms in the matrix Gla protein gene have been associated with hand OA( Reference Misra, Booth and Crosier 37 ), and serum levels of undercarboxylated osteocalcin may be associated with synovitis in knee OA( Reference Naito, Watari and Obayashi 38 ). Niacinamide, a form of vitamin B3, has been examined in a pilot scale clinical study of OA and reported to show improvements at 12 weeks( Reference Jonas, Rapoza and Blair 39 ).
An association between dietary magnesium intake and knee OA was demonstrated in the Johnston County Osteoarthritis Project, but this varied with ethnicity( Reference Qin, Shi and Samai 40 ). This is supported by data from the Twins UK registry where discordant twin pair analysis showed a decrease in magnesium in co-twins with OA( Reference Hunter, Hart and Snieder 41 ). Selenium has been implicated the osteoarthropathy of Kashin–Beck disease; meta-analysis of supplementation studies supports the benefit of supplementation in children, but highlights the low quality of methodology( Reference Zou, Liu and Wu 42 ).
Lipid metabolism
Recent studies have suggested that OA may be part of metabolic syndrome( Reference Zhuo, Yang and Chen 43 ). Alterations in lipid metabolism may be key to this, with population-based studies suggesting that serum cholesterol is a risk factor for OA (reviewed in( Reference Gkretsi, Simopoulou and Tsezou 44 )). Population studies also suggest that statin use is associated with a reduction in OA incidence and/or progression( Reference Clockaerts, Van Osch and Bastiaansen-Jenniskens 45 , Reference Kadam, Blagojevic and Belcher 46 ), but studies of pain and function in patients with OA have shown no association( Reference Riddle, Moxley and Dumenci 47 ). This area therefore remains controversial. It has been reported that high levels of fat and fatty acids are found in osteoarthritic joint tissues and that this is associated with pathology( Reference Lippiello, Walsh and Fienhold 48 , Reference Plumb and Aspden 49 ). n-3 PUFA, but not n-6 PUFA were found to be associated with the specific loss of cartilage in the Multicenter Osteoarthritis Study population of people at risk of OA( Reference Baker, Matthan and Lichtenstein 50 ). In healthy individuals, consumption of SFA or n-6 PUFA (but not n-3 PUFA) was associated with an increased risk of bone marrow lesions( Reference Wang, Davies-Tuck and Wluka 51 , Reference Wang, Wluka and Hodge 52 ). In animal models, a high-fat diet accelerated progression of OA( Reference Mooney, Sampson and Lerea 53 ), while n-3 PUFA reduced disease( Reference Knott, Avery and Hollander 54 ). Studies in isolated chondrocytes showed that n-3 PUFA inhibited IL-1-induced MMP3, MMP13, ADAMTS4, ADAMTS5 and COX2 (matrix metalloproteinase (MMP); a disintegrin and metalloproteinase domain with thrombospondin motifs (ADAMTS); cyclooxygenase (COX)) expression, while n-6 PUFA had no effect( Reference Hurst, Rees and Randerson 55 , Reference Zainal, Longman and Hurst 56 ). A small improvement in OA in dogs was seen with fish oil supplementation( Reference Hielm-Bjorkman, Roine and Elo 57 , Reference Roush, Dodd and Fritsch 58 ). Interestingly, a supplement rich in fish oil, Phytalgic, was shown to improve function and pain in OA patients( Reference Jacquet, Girodet and Pariente 59 ), although the design of this trial has been criticised( Reference Christensen and Bliddal 60 ).
Diet-derived bioactives
Typically, foods contain multiple bioactive compounds and these can impact upon many biological pathways( Reference Ameye and Chee 61 ). Diet-derived bioactives can be classified into several groups, e.g. flavonoids (and related compounds), carotenoids, plant sterols, glucosinolates and others( Reference Denny and Buttriss 62 ).
Flavonoids
Flavonoids are polyphenols and include flavan-3-ols, flavonols, flavones, isoflavones, flavanones and anthocyanins. More than 6000 different flavonoids have been found and they are widely distributed in plants, with several hundred found in edible plants( Reference Falcone Ferreyra, Rius and Casati 63 , Reference Manach, Scalbert and Morand 64 ).
Flavonols
Flavonols are found in many foods and are exemplified by quercetin, myricetin and kaempferol( Reference Manach, Scalbert and Morand 64 ). Quercetin and kaempferol showed no activity against IL-1-induced MMP13 levels in SW1353 chondrosarcoma cells( Reference Lim, Park and Kim 65 ). However, Lay et al. report that quercetin is able to block aggrecan loss from articular cartilage potentially via inhibition of ADAMTS4 and ADAMTS5( Reference Lay, Samiric and Handley 66 ) and Lee et al. show that myricetin can inhibit IL-1 induction of MMP1 from a synovial cell line( Reference Lee and Choi 67 ).
Flavones
In fruit and vegetables, flavones are found in celery and parsley, mainly luteolin and apigenin. In the skin of citrus fruit, polymethoxylated flavones are also found, e.g. tangeretin, nobiletin and sinensetin( Reference Manach, Scalbert and Morand 64 ). Luteolin and nobiletin have been shown to inhibit aggrecanases ADAMTS4 and ADAMTS5, both in vitro ( Reference Imada, Lin and Liu 68 , Reference Moncada-Pazos, Obaya and Viloria 69 ) and in vivo ( Reference Imada, Lin and Liu 68 ). Luteolin appears to be selective as a better ADAMTS than MMP inhibitor( Reference Moncada-Pazos, Obaya and Viloria 69 ), it also has anti-inflammatory activity, which could play a role in chondroprotection( Reference Lopez-Lazaro 70 ). Nobiletin, tangeretin and sinensetin all repress the IL-1 induction of MMP9 in synovial cells, with nobiletin also active in chondrocytes( Reference Ishiwa, Sato and Mimaki 71 ). Apigenin was shown to be a potent inhibitor of IL-1-induced MMP13 expression in SW1353 chondrosarcoma cells, potentially via activator protein 1 and the JAK/STAT (Janus kinase (JAK) and signal transducer and activator of transcription (STAT)) pathway, with no activity against NF-κB( Reference Lim, Park and Kim 65 ). It has also been shown to block IL-1-induced glycosaminoglycan release( Reference Lim, Park and Kim 65 ) and hyaluronan release( Reference Durigova, Roughley and Mort 72 ) from cartilage explants in vitro.
Flavan-3-ols
These exist as both monomer (catechins) and polymer (proanthocyanidins) forms( Reference Manach, Scalbert and Morand 64 ). Green tea polyphenols were shown to be effective in a model of inflammatory arthritis( Reference Haqqi, Anthony and Gupta 73 ). Catechins from green tea (and also present in other foods including dark chocolate) can inhibit cartilage degradation in vitro, particularly those containing a gallate ester( Reference Adcocks, Collin and Buttle 74 ). Epigallocatechin gallate and epicatechin gallate have been shown to be effective (submicromolar) inhibitors of ADAMTS4 and ADAMTS5 aggrecanase activity, indeed significantly more than their ability to inhibit MMP1 and MMP13 collagenase activity( Reference Vankemmelbeke, Jones and Fowles 75 ). Other anti-inflammatory activities have been described (e.g.( Reference Akhtar and Haqqi 76 )) that suggests promise in OA (reviewed in( Reference Ahmed 77 )), but no human clinical trials have been performed to date.
While not a diet-derived bioactive, Flavocoxid, a mixture of baicalin (a flavone) from Scutellaria baicalensis and catechins from Acacia catechu, is marketed as Limbrel, a ‘medical food’ which inhibits COX2 and 5-lipoxygenase( Reference Burnett, Jia and Zhao 78 ). An assessment of the major catechins from A. catechu suggests that they are predominantly those described earlier found in green tea( Reference Shen, Wu and Wang 79 ). Small clinical trials have suggested that Limbrel shows efficacy in OA (e.g.( Reference Levy, Khokhlov and Kopenkin 80 )), but recently severe liver toxicity has been described in some patients( Reference Chalasani, Vuppalanchi and Navarro 81 ).
A grape seed proanthocyanidin extract is protective in the monosodium iodoacetate model of OA in the rat, showing chondroprotection and decreased pain( Reference Woo, Joo and Jung 82 ). Specifically, procyanidin B3 abrogates cartilage destruction and heterotopic cartilage formation in a surgical model of OA in the mouse( Reference Aini, Ochi and Iwata 83 ). It was shown to block IL-1 repression of matrix gene expression in vitro and also decrease inducible nitric oxide synthase in vitro and in vivo ( Reference Aini, Ochi and Iwata 83 ).
Another mixture not derived from the diet, Pycnogenol is a pine bark extract rich in procyanidins( Reference D'Andrea 84 ). It has been reported to inhibit NF-κB activation and the activity of some MMP( Reference Grimm, Chovanova and Muchova 85 , Reference Grimm, Schafer and Hogger 86 ). Three small clinical trials have been performed in OA with positive outcomes reported (e.g.( Reference Belcaro, Cesarone and Errichi 87 , Reference Cisar, Jany and Waczulikova 88 )). However, a Cochrane review of Pycnogenol in chronic diseases (including OA) stated that it was not possible to reach definite conclusions on either efficacy or safety of Pycnogenol( Reference Schoonees, Visser and Musekiwa 89 ).
Anthocyanins
Anthocyanins are responsible for the red/blue pigmentation in fruits and vegetables( Reference Manach, Scalbert and Morand 64 ). To date most studies have been performed using fruit juices or extracts that are rich in anthocyanins. A recent clinical trial examined tart cherry juice in patients with knee OA( Reference Schumacher, Pullman-Mooar and Gupta 90 ). No difference in disease scores compared with placebo was uncovered, but high-sensitivity C-reactive protein was significantly lowered and this was associated with decreased score( Reference Schumacher, Pullman-Mooar and Gupta 90 ). Pomegranate juice or extracts, which have been reported to contain anthocyanins and many other flavonoids including flavanols, have been shown to inhibit IL-1-induced MMP expression in chondrocytes via inhibition of MAP kinases and NF-κB( Reference Ahmed, Wang and Hafeez 91 – Reference Jean-Gilles, Li and Vaidyanathan 93 ). Such extracts also show efficacy in the monosodium iodoacetate model of OA in mice( Reference Hadipour-Jahromy and Mozaffari-Kermani 94 ). Raspberry extract( Reference Jean-Gilles, Li and Ma 95 ) and red orange extract( Reference Frasca, Panico and Bonina 96 ) have also been reported to have some efficacy in vitro and in vivo.
Isoflavones
Isoflavones are diphenolic compounds with structural similarity to oestrogens, and are consequently referred to as phytoestrogens. They are found mainly in legumes and soya is a major source of isoflavones in the diet( Reference Manach, Scalbert and Morand 64 ). Data in chondrocytes show that one isoflavone, genistein, reduces the production of inflammatory molecules such as COX2 and nitric oxide( Reference Hooshmand, Soung do and Lucas 97 ). Extracellular matrix synthesis in cartilage may increase or decrease, potentially with increasing dose( Reference Claassen, Briese and Manapov 98 , Reference Yu, Xing and Dong 99 ). In the rat inflammatory collagen-induced arthritis model, soya protein appears to be protective( Reference Mohammad Shahi, Rashidi and Mahboob 100 ), however, no significant effect of soya intake was measurable on OA severity in Cynomolgus monkeys( Reference Ham, Loeser and Lindgren 101 ). One human study suggested beneficial effects of soya protein supplementation on function, symptoms and biochemical markers of OA, particularly in men( Reference Arjmandi, Khalil and Lucas 102 ).
Flavanones
Flavanones are present in the diet at high concentrations only in citrus fruits including naringenin from grapefruit, hesperetin from oranges and eriodictyol from lemons( Reference Manach, Scalbert and Morand 64 ). No effect was seen for naringenin on IL-1-induced MMP13 production in SW1353 chondrosarcoma cells( Reference Lim, Park and Kim 65 ). However, hesperetin, its glycoside hesperidin or its derivatives, show efficacy in inflammatory models of arthritis( Reference Choi and Lee 103 – Reference Umar, Kumar and Sajad 105 ). Red orange juice extract showed repression of inflammatory molecules in chondrocytes as mentioned earlier( Reference Frasca, Panico and Bonina 96 ).
Carotenoids
β-Carotene is the most widely known carotenoid and is a precursor to vitamin A( Reference Maiani, Caston and Catasta 106 ). Vitamin A and its derivatives, retinoids, are known to have profound effects on cartilage and the skeleton and may contribute to OA( Reference Davies, Ribeiro and Downey-Jones 107 ). The Framingham study identified a weak protective association between intake of β-carotene and the progression of radiographic knee OA( Reference McAlindon, Jacques and Zhang 14 ). A case–control study in the Johnston Couny Osteoarthritis Project examined the association between serum levels of several carotenoids (lutein, zeaxanthin, β-cryptoxanthin, lycopene, α-carotene and β-carotene) and OA( Reference De Roos, Arab and Renner 108 ). People with high levels of lutein or β-cryptoxanthin were less likely to have knee OA, while those with high levels of trans-β-carotene or zeaxanthin were more likely to have knee OA. Similarly, a cross-sectional study in a Japanese population with radiographic knee OA examined the association between serum levels of several carotenoids (lutein, zeaxanthin, cantaxanthin, cryptoxanthin, lycopene, α-carotene and β-carotene) and OA, but found nothing significant( Reference Seki, Hasegawa and Yamaguchi 109 ). It is worth noting that there is evidence that β-cryptoxanthin is associated with a decreased risk of inflammatory arthritis (e.g.( Reference Pattison, Symmons and Lunt 110 )). In healthy, middle-aged people, lutein and zeaxanthin intake were associated with decreased risk of cartilage defects on MRI and β-cryptoxanthin intake was inversely associated with tibial plateau bone area( Reference Wang, Hodge and Wluka 17 ).
Plant sterols
As discussed earlier, there is a positive association between serum cholesterol and OA, with statin use appearing to show efficacy in disease incidence and/or progression. Intake of plant phytosterols/stanols significantly reduce LDL cholesterol and total cholesterol in intervention trials( Reference Kamal-Eldin and Moazzami 111 , Reference Wu, Fu and Yang 112 ) and of the three phytosterols tested, (stigmasterol, sitosterol and campesterol), stigmasterol bound best to chondrocyte membranes( Reference Gabay, Sanchez and Salvat 113 ). It inhibited IL-1-induced MMP and ADAMTS4 expression, although had no effect on ADAMTS5, potentially via its ability to inhibit NF-κB activation( Reference Gabay, Sanchez and Salvat 113 ). Intra-articular injection of stigmasterol was shown to suppress MMP expression and reduce cartilage degradation in a rabbit anterior cruciate ligament transection model of OA( Reference Chen, Yu and Hu 114 ).
Glucosinolates
Glucosinolates are found in cruciferous vegetables and are the precursors of isothiocyanates. Broccoli is rich in glucoraphanin, and when the vegetable is chopped or chewed, it is exposed to the action of an enzyme myrosinase to yield sulforaphane, the isothiocyanate. In chondrocytes, sulforaphane was initially shown to decrease shear stress-induced apoptosis( Reference Healy, Lee and Gao 115 ). More recently, it has been shown to exhibit pro-survival and anti-apoptotic activities when cell death is induced by a variety of stimuli( Reference Facchini, Stanic and Cetrullo 116 ). Sulforaphane has been shown to block IL-1 and TNFα induction of MMP1 and MMP13 expression, as well as PGE2 and nitric oxide in chondrocytes( Reference Kim, Yeo and Kim 117 ) and inhibit cartilage degradation in vitro ( Reference Kim, Yeo and Jung 118 ). Later work showed that it was effective in inhibiting expression of ADAMTS4 and ADAMTS5, and abrogating cartilage destruction in the ‘destabilisation of the medial meniscus’ model of OA in the mouse, acting as a direct inhibitor of NF-κB( Reference Davidson, Jupp and de Ferrars 119 ).
Resveratrol
Resveratrol is a plant-derived phenol of the stilbenoid class, found at high concentrations in the skin of red grapes and in red wine. It has come to the fore as an activator of the histone deacetylase Sirt1, which has important roles in cell survival and as a mimic of caloric restriction that extends lifespan in many models( Reference Lam, Peterson and Ravussin 120 ). Sirt1 is intimately involved in OA with deletion of Sirt1 in mice causing more rapid development of OA in a post-surgical model( Reference Matsuzaki, Matsushita and Takayama 121 ). Resveratrol decreases OA score when directly injected intraarticularly in the rabbit anterior cruciate ligament transection model of OA( Reference Elmali, Esenkaya and Harma 122 , Reference Wang, Gao and Chen 123 ). It is an NF-κB inhibitor in chondrocytes and blocks inflammation and apoptosis( Reference Csaki, Keshishzadeh and Fischer 124 – Reference Shakibaei, Csaki and Nebrich 126 ). It has also been shown to decrease proteolysis (e.g. MMP and ADAMTS) and enhance extracellular matrix synthesis( Reference Im, Li and Chen 127 ).
Interestingly, resveratrol has been shown to display synergistic effects on chondrocyte phenotype and apoptosis with curcumin (see later)( Reference Csaki, Mobasheri and Shakibaei 128 , Reference Shakibaei, Mobasheri and Buhrmann 129 ). These compounds both inhibit NF-κB, but are known to act via different mechanisms.
Curcumin
Curcumin is the major curcuminoid found in the spice, turmeric. It has been shown to be an NF-κB inhibitor( Reference Singh and Aggarwal 130 ), and used in chondrocytes as an inhibitor of oncostatin M-, IL-1- and TNFα-induced signalling( Reference Li, Dehnade and Zafarullah 131 – Reference Liacini, Sylvester and Li 133 ). Here it was shown to inhibit c-Jun N-terminal kinase, activator protein 1, STAT and mitogen-activated protein kinase signalling, to inhibit expression of key MMP in cartilage and proposed to have potential clinical utility. Innes et al. used a turmeric extract in a clinical trial of OA in the dog, with clinical assessments showing significant improvement( Reference Innes, Fuller and Grover 134 ). The anti-catabolic effects of curcumin in human articular chondrocytes were confirmed( Reference Schulze-Tanzil, Mobasheri and Sendzik 135 ) and its impact extended to include anti-apoptotic activity( Reference Shakibaei, Schulze-Tanzil and John 136 ), pro-anabolic effects on matrix expression( Reference Lay, Samiric and Handley 66 , Reference Shakibaei, Schulze-Tanzil and John 136 ), inhibition of COX2 expression and other inflammatory mediators( Reference Mathy-Hartert, Jacquemond-Collet and Priem 137 , Reference Shakibaei, John and Schulze-Tanzil 138 ). Efficacy was also shown in cartilage explants( Reference Lay, Samiric and Handley 66 , Reference Clutterbuck, Mobasheri and Shakibaei 139 ) and murine models of inflammatory arthritis( Reference Mun, Kim and Kim 140 ), although not yet OA. Curcumin itself has poor solubility and bioavailability( Reference Henrotin, Clutterbuck and Allaway 141 ), but a curcumin–phophatidylcholine complex (Meriva), designed to overcome this, has shown some efficacy in small-scale clinical trials( Reference Belcaro, Cesarone and Dugall 142 , Reference Belcaro, Cesarone and Dugall 143 ). As discussed earlier, a thorough understanding of mechanism of action has led to experiments showing synergy between curcumin and resveratrol( Reference Csaki, Mobasheri and Shakibaei 128 , Reference Shakibaei, Mobasheri and Buhrmann 129 ).
Avocado-soyabean unsaponifiables
While not truly dietary-derived, avocado-soyabean unsaponifiables (ASU), Piascledine, has been developed by Laboratoire Expanscience and is the unsaponifiable fraction of one-third avocado oil and two-thirds soyabean oil. It is a mixture of tocopherols, plant sterols and other molecules( Reference Msika, Baudouin and Saunois 144 ). A recent moderate-sized trial of Piascledine in hip OA (the ERADIAS study) over 3 years showed that while there was no significant difference in mean joint space width loss between treatment and placebo, there were significantly less progressors in the treatment group. There was no difference in clinical outcomes including pain or analgesic/non-steroidal anti-inflammatory drug use( Reference Maheu, Cadet and Marty 145 ). This was somewhat similar to an earlier smaller study examining structural modification( Reference Lequesne, Maheu and Cadet 146 ), but very different from other earlier trials, where ASU demonstrated reductions in pain, functional disability or non-steroidal anti-inflammatory drug use in patients with hip or knee OA over 3–6 months( Reference Appelboom, Schuermans and Verbruggen 147 – Reference Maheu, Mazieres and Valat 149 ). In a dog anterior cruciate ligament transection model of OA, ASU reduced disease severity and decreased MMP13 production( Reference Boileau, Martel-Pelletier and Caron 150 ), although in an ovine model of post-meniscectomy OA, ASU was described to have a ‘subtle, but statistically significant’ effect on cartilage( Reference Cake, Read and Guillou 151 ). In vitro data showed that ASU exhibit anti-catabolic (MMP expression), anti-inflammatory (PGE2, nitric oxide, COX2) and pro-anabolic (type II collagen and aggrecan synthesis) in chondrocytes. It has also been shown to inhibit NF-κB activity( Reference Gabay, Gosset and Levy 152 – Reference Henrotin, Sanchez and Deberg 154 ). It should also be pointed out that other formulations of ASU exist and one from Nutramax has been shown to have similar in vitro activity in chondrocytes( Reference Au, Al-Talib and Au 155 ). Data from equine chondrocytes suggest that this ASU can act synergistically with epigallocatechin gallate( Reference Heinecke, Grzanna and Au 156 ). The relative merits of each preparation have been the subject of debate( Reference Msika, Baudouin and Saunois 144 , Reference Frondoza 157 , Reference Henrotin 158 ).
Ginger
There have been several small clinical trials exploring the efficacy of ginger extract in the treatment of OA. Trials using Zingiber officinale extract showed variable outcome and a review found that evidence for its efficacy in OA was weak( Reference Leach and Kumar 159 ). A mixture of extracts from Z. officinale and Alpinia galangal used in a short (6-week) study showed a significant effect in reducing clinical symptoms( Reference Altman and Marcussen 160 ). In vitro research suggests that ginger extract can decrease production of inflammatory mediators from chondrocytes( Reference Shen, Hong and Kim 161 ) and synoviocytes( Reference Ribel-Madsen, Bartels and Stockmarr 162 ).
Sulphur-containing compounds
A cross-sectional study in twins demonstrated that consumption of both allium vegetables and also non-citrus fruits showed a protective association with hip OA( Reference Williams, Skinner and Spector 163 ). Furthermore, diallyl disulphide, a compound from garlic, was shown to inhibit IL-1-induced MMP1, MMP3 and MMP13 expression( Reference Williams, Skinner and Spector 163 ). Diallyl sulphide has also been shown to block expression of these enzymes and ameliorate cartilage destruction when administered intraarticularly in the rabbit anterior cruciate ligament transection model of OA( Reference Chen, Tang and Bao 164 ).
Others
Interestingly, data on the progression of knee OA, coming from the Osteoarthritis Initiative showed that frequent soft drink consumption is associated with increased disease progression in men, independent of obesity( Reference Lu, Ahmad and Zhang 165 ). This obviously requires replication. An extract of edible bird's nest (which is made from swiftlet saliva), has been shown to have anti-catabolic, anti-inflammatory and pro-anabolic activity on human osteoarthritic chondrocytes( Reference Chua, Lee and Nagandran 166 ). Sesamin, a lignan from sesame seeds has been reported to be chondroprotective in an explant assay, decreasing MMP expression and activation( Reference Phitak, Pothacharoen and Settakorn 167 ). An extract of a variety of mint which overexpressed rosmarinic acid inhibits lipopolysaccharide-induced glycosaminoglycan release and inflammatory mediators from porcine cartilage explants( Reference Pearson, Fletcher and Kott 168 ).
Conclusions
There are many compounds present in the habitual diet, which have been shown to have activity in both laboratory models of OA and/or human disease. Where examined, many of these compounds appear to be inhibitors of the NF-κB pathway. This signalling pathway has been shown to play a role in the development and progression of OA( Reference Marcu, Otero and Olivotto 169 ). Two studies suggest that using a combination of compounds, which inhibit the NF-κB pathway via different mechanisms gives a synergistic response( Reference Csaki, Mobasheri and Shakibaei 128 , Reference Shakibaei, Mobasheri and Buhrmann 129 ). It would thus be important to understand the mode of NF-κB inhibition for all compounds with this activity. In order to achieve synergy, it will also be important to discover compounds which do not act via this mechanism. Since habitual dietary intakes vary widely, an understanding of food combinations, which protect the joint, may be key and this may also be a means to develop specific food products or offer targeted advice to reduce risk.
Basic science provides information on the mechanisms of cartilage protection in healthy tissue and the prevention of cartilage destruction in disease. The design of randomised clinical trials in the longer term needs to include ‘at risk’ populations (in which incidence of OA can be used as an outcome measure), as well as patients with existing OA. This is in line with the current European Food Standards Agency recommendations that the design of human trials must demonstrate a preventative effect on the healthy joint, separately from an impact on established OA per se to establish claims in both areas.
In summary, diet offers a route by which the health of the joint can be protected and OA incidence or progression decreased. In a chronic disease, with risk factors increasing in the population and with no pharmaceutical cure, an understanding of this will be crucial.
Acknowledgements
We would like to thank all members of the Clark laboratory present and past and our collaborators in research related to this review.
Financial Support
Research in this area in Clark laboratory is funded by the BBSRC Diet and Health Research Industry Club grant BB/I006060/1 and PhD studentships BB/J500112/1, Arthritis Research UK grant 19371, Orthopaedic Research UK grant 487 and previously Dunhill Medical Trust grant R73/0208. These funders had no role in the design, analysis or writing of this article.
Conflicts of Interest
None.
Authorship
All authors have contributed to writing and/or critically reviewing and editing the manuscript.
