Dietary Supplements in OA: Real Opportunity or Utopia?
Ali Mobasheri, D.Phil.
Musculoskeletal Research Group
School of Veterinary Medicine and Science
Faculty of Medicine and Health Sciences
Concurrent Session 5 - PAIN, CLINICAL AND PATHOPHYSIOLOGICAL ASPECTS Friday 24 September 2010
Dietary Supplements in OA: ‘Un Amour Impossible?’
• Management of OA primarily involves symptomatic pain relief– Analgesics– Non-steroidal anti-inflammatory drugs (NSAIDs)
• However, pharmacotherapy with conventional drugs does not influence disease progression and can be associated with significant side effects
• Therefore, there is an acute need for alternative remedies for OA
• Nutritional supplements have been reported to improve symptoms and reduce NSAID usage– But there is no conclusive proof of efficacy
Dietary Supplements in OA
• Glucosamine and chondroitin sulfate• Vitamins (C, D, E and beta carotene)• Polyunsaturated fatty acids (PUFAs)
– Omega-3 fatty acids• Herbal and botanical extracts
– Polyphenols, phytochemicals and phytoestrogens• Green tea catechins• Curcumin• Resveratrol
Nutrigenomics
• The study of the effects of foods and food constituents on gene expression
van Ommen (2004) Nutrition 20, 4-8
Nutrigenomics and Personalized Nutrition
• Nutrigenomics is a form of personalized nutrition* that involves tailoring diets to an individual’s genetic makeup, considering genetic variation, allergies and intolerances
• An important aim of nutrigenomic research is defining the relationship between genes and nutrients from basic biology to clinical states
*International Society of Nutrigenetics/Nutrigenomics (ISNN)http://www.isnn.info/
Nutrigenomics and Systems Biology
• Nutrigenomics and systems biology use the same models and tools to identify biomarkers and therapeutic targets
van Ommen (2004) Nutrition 20, 4-8
What is the evidence linking nutrition and disease?
• Malnutrition results in poor bone development
• Evidence from Dutch famine cohort study and subsequent research suggests that:– we are what we eat– we are what our mothers ate
ObesityCalories in = Calories consumed Normal weight
Calories in > Calories consumed Obese state
Obesity and OA
• Strong evidence supports a link between overweight, obesity and OA
• Obesity: complex metabolic and inflammatory syndrome
• Adipokines, (adipocytokines) play important roles in the onset of disease
• Lifestyle changes for OA patients– Weight loss, calorie restriction and moderate (non-
ballistic) exercise
Gabay, Hall, Berenbaum, Henrotin and Sanchez (2008) Joint Bone Spine 75, 675-9.Abramson and Attur (2009) Arthritis Res Ther 11, 227.Iannone and Lapadula (2010) Curr Drug Targets 11, 586-98.
Evidence for Nutritional Intervention from Studies on RA Patients
• Dietary intervention clearly has a place in rheumatology and allows patients some control over their own disease– 30-40% of rheumatoid arthritis patients benefit
from excluding foods individually identified during the reintroduction phase of an elimination diet
Rayman and Pattison (2008) Best Pract Res Clin Rheumatol 22, 535-561.
Evidence for Nutritional Intervention in OA
• Controversial – there is a need for systematic scientific evaluation of the claims made for dietary supplements
• Complicated by occasional reports of toxicity from contaminants
• Lack of research on intestinal absorption, bioavailability and clearance of dietary supplements
• Combinations of dietary supplements with NSAIDs have shown beneficial trends– Some studies suggest that the trends are not significant– Others suggest that some dietary supplements can reduce
NSAID usage in patients
McAlindon and Biggee (2005) Curr Opin Rheumatol. 17, 647-52.Ameye and Chee (2006) Arthritis Res Ther. 8, R127.
Phytalgic: a food supplement containing fish-oil, vitamin E and Urtica dioica
NF-kB: a Therapeutic Target in OA
• Nuclear factor-kappaB (NF-kB) - involved in the pathogenesis of OA and RA
• Targeting the NF-kB signaling pathway:– New therapeutic strategies for developing new
arthritis drugs– Must target cartilage and synovium to avoid adverse
systemic effects
Vincenti and Brinckerhoff (2002) Arthritis Res 4, 157-64.Berenbaum (2004) Curr Opin Rheumatol 16, 616-22.Roman-Blas and Jimenez SA (2006) Osteoarthritis Cartilage 14, 839-48. Saklatvala (2007) Curr Drug Targets 8, 305-13.Marcu, Otero, Olivotto, Borzi and Goldring (2010) Curr Drug Targets 11, 599-613.
Curcumin - Diferuloylmethane
• Curcumin is one of three curcuminoids obtained by solvent extraction from dried turmeric roots
• Used globally for food coloring. It has potent antioxidant, anti-inflammatory, antiviral and antifungal properties
• It exerts anti-inflammatory activity by inhibition of a number of different molecules and pathways that play an important role in inflammation (i.e. NF-kB)
The Curcumin/AP-1/NF-kB Axis in Inflammatory Responses in Joint Cells
• Naturally occurring plant-derived compounds such as curcumin can modulate NF-kB activity without undesired systemic effects
Henrotin et al., (2010) Osteoarthritis Cartilage 18, 141-9.
Effects of Curcumin on TNF Signaling
Mobasheri, Aldinger and Shakibaei (2011) Role of Inflammation in Rheumatic DiseasesIn: Inflammation, Life Style and Chronic Diseases: The Silent Link. CRC PressISBN: 978-1-4398398-9-8
Clinical Trial of Curcumin in RA
• Curcumin (Longvida™) - randomized, placebo-controlled, phase 0 clinical trial employing 40 subjects
• Cross-over design lasting up to 8 months• Start Date: January 2010, Completion Date:
January 2011• Location: University of California, Los Angeles• ClinicalTrials.gov Identifier: NCT00752154
Source: http://clinicaltrials.gov/
Curcumin inhibits GAG and PGE2 release from IL-1b stimulated cartilage explants
Clutterbuck, A (2010) PhD Thesis. University of NottinghamClutterbuck et al., (unpublished observations)
Comparing the effects of curcumin and carprofen on GAG and PGE2 release from
IL-1b stimulated cartilage explants
Clutterbuck, A (2010) PhD Thesis. University of NottinghamClutterbuck et al., (unpublished observations)
Resveratrol - Trans-3,5,4'-trihydroxystilbene
• Flavonol belonging to the group of flavonoids• Produced by plants as a defence against fungal disease• Antioxidant but weaker that quercetin and epicatechin• Present in many plants and fruits, including red grapes
(and red wine), eucalyptus, spruce, blueberries, mulberries, peanuts, giant Japanese knotweed
Scientific Basis for the Study of Resveratrol: Modulation of Sirtuins
• Members of the sirtuin family regulate epigenetic gene silencing
• Sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity
• In human cells resveratrol increases cell survival by stimulating SIRT1-dependent deacetylation of p53
• In yeast cells resveratrol stimulates Sir2, increasing DNA stability and extending lifespan by up to 70%
Howitz et al., (2003) Nature 425, 191-196
Biological Functions of SIRT1
Sirtuins – Novel Therapeutic Targets to Treat Age-Associated Diseases
Lavu et al., (2008) Nature Reviews Drug Discovery 7, 841-853
Activation of SIRT1 by Resveratrol, Calorie Restriction and Fasting
SirT1 Activates IGFR Pathway and Suppresses Apoptosis in Chondrocytes
Gagarina et al., (2010) ARTHRITIS & RHEUMATISMVol. 62, No. 5, May 2010, pp 1383–1392
Effects of Resveratrol on Human Chondrocytes
• Resveratrol inhibits – IL-1b–induced PGE2 and LTB4
– IL-1b–induced induction of the apoptotic markers cytochrome C and annexin V
– Mitochondrial membrane depolarization, loss of mitochondrial biomass, and IL-1b–induced ATP depletion
Resveratrol Suppresses IL-1b Signaling and Apoptosis in Chondrocytes
• Resveratrol blocks IL-1b induced apoptosis in human chondrocytes
Curcumin and Resveratrol: Evidence for Synergistic Activity
Curcumin Enhances Chondrogenesis of Mesenchymal Stem Cells in vitro
• Insert copy of Arthritis Research and Therapy paper
In vitro models of cartilage as biomimetic systems for high-
throughput screening of nutrient-derived compounds and combinations of herbal
extracts
Explant Culture• Advantages:
– Chondrocytes remain phenotypically stable in their native matrix
– Ideal for studies of extracellular matrix synthesis and degradation• GAG and collagen assays
– Suitable for proteomic work and studying anti-inflammatory drugs and plant derived compounds
Curcumin and Resveratrol Counteract GAG Release in LPS Treated Cartilage Explants
% G
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High-Throuoghput Proteomic Study of the Cartilage Secretome
Commonly Identified Proteins:Canine Cartilage Secretome
Poster 121Hillier et al.,OARSI 2010
Proteins identified using the SwissProt 51.6 database
Proteins identified using the SwissProt 51.6 database
Commonly Identified Proteins:Equine Cartilage Secretome
Poster 503 Clutterbuck et al.,OARSI 2010
Western Blot Validation
Poster 503Clutterbuck et al.,OARSI 2010
Heinegård D. (2009) Int J Exp Pathol. 90, 575-86
Conclusions I• Whether supplements can be effectively and safely
recommended to reduce NSAID usage is unclear and requires more high-quality research
• This area will remain controversial if there is substantial commercial involvement in research and in influencing publications
• Ambiguous results or failure of clinical trials can make matters worse
Conclusions II• There is potential for high quality basic research
into gene nutrient interactions• However, subsequent clinical studies will need to
select more homogeneous patient populations• The marriage between dietary supplements and
OA therapy can be a viable one as long as the relationship involves hypothesis driven basic research followed by well-designed, rigorous and unbiased clinical trials
• L'amour est possible mais très difficile…
A few words of caution…
A few words of caution…
Acknowledgements: Postgraduate Students and Funding
Abigail ClutterbuckAdam Williams
Jasmine Penny
Enrico Glaab
Acknowledgements: Collaborators
Professor Mehdi ShakibaeiLMU Munich, Germany
Dr. Pat HarrisDr. David Allaway
Dr. Julia SmithDr. John Kelly
Dr. Susan LiddellDr. Jaume BacarditProfessor Sean MayProfessor Kevin Shakesheff
Professor Yves HenrotinUniversity of Liège, Belgium
Professor AlexandrinaFerreira MendesCoimbra, Portugal
Thank you for your attention