Oarsi 2010 Presentation A. Mobasheri

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

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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