Concurrent Session 5 - PAIN, CLINICAL AND PATHOPHYSIOLOGICAL ASPECTS <br />Friday 24 September 2010<br />Dietary Supplemen...
Dietary Supplements in OA: ‘Un Amour Impossible?’ <br />Management of OA primarily involves symptomatic pain relief<br />A...
Dietary Supplements in OA<br />Glucosamine and chondroitin sulfate<br />Vitamins (C, D, E and beta carotene)<br />Polyunsa...
Nutrigenomics<br />The study of the effects of foods and food constituents on gene expression<br />van Ommen (2004) Nutrit...
Nutrigenomics and Personalized Nutrition<br />Nutrigenomics is a form of personalized nutrition* that involves tailoring d...
Nutrigenomics and Systems Biology<br />Nutrigenomics and systems biology use the same models and tools to identify biomark...
What is the evidence linking nutrition and disease?<br />Malnutrition results in poor bone development<br />Evidence from ...
Obesity<br />Calories in = Calories consumed		Normal weight<br />Calories in > Calories consumed		Obese state<br />
Obesity and OA<br />Strong evidence supports a link between overweight, obesity and OA<br />Obesity: complex metabolic and...
Evidence for Nutritional Intervention from Studies on RA Patients<br />Dietary intervention clearly has a place in rheumat...
Evidence for Nutritional Intervention in OA<br />Controversial – there is a need for systematic scientific evaluation of t...
Phytalgic: a food supplement containing fish-oil, vitamin E and Urtica dioica<br />
NF-kB: a Therapeutic Target in OA<br />Nuclear factor-kappaB (NF-kB) - involved in the pathogenesis of OA and RA<br />Targ...
Curcumin - Diferuloylmethane<br />Curcumin is one of three curcuminoids obtained by solvent extraction from dried turmeric...
The Curcumin/AP-1/NF-kB Axis in Inflammatory Responses in Joint Cells<br />Naturally occurring plant-derived compounds suc...
Effects of Curcumin on TNF Signaling<br />Mobasheri, Aldinger and Shakibaei (2011) Role of Inflammation in Rheumatic Disea...
Clinical Trial of Curcumin in RA<br />Curcumin (Longvida™) - randomized, placebo-controlled, phase 0 clinical trial employ...
Curcumin inhibits GAG and PGE2 release from IL-1b stimulated cartilage explants <br />Clutterbuck, A (2010) PhD Thesis. Un...
Comparing the effects of curcumin and carprofen on GAG and PGE2 release from IL-1b stimulated cartilage explants<br />Clut...
Resveratrol - Trans-3,5,4'-trihydroxystilbene<br />Flavonol belonging to the group of flavonoids<br />Produced by plants a...
Scientific Basis for the Study of Resveratrol: Modulation of Sirtuins<br />Members of the sirtuin family regulate epigenet...
Biological Functions of SIRT1<br />
Sirtuins – Novel Therapeutic Targets to Treat Age-Associated Diseases<br />Lavu et al., (2008) Nature Reviews Drug Discove...
Activation of SIRT1 by Resveratrol, Calorie Restriction and Fasting<br />
SirT1 Activates IGFR Pathway and Suppresses Apoptosis in Chondrocytes<br />Gagarina et al., (2010) ARTHRITIS & RHEUMATISM<...
Effects of Resveratrol on Human Chondrocytes<br />Resveratrol inhibits <br />IL-1b–induced PGE2 and LTB4 <br />IL-1b–induc...
Resveratrol Suppresses IL-1b Signaling and Apoptosis in Chondrocytes<br />Resveratrol blocks IL-1b induced apoptosis in hu...
Curcumin and Resveratrol: Evidence for Synergistic Activity<br />
Curcumin Enhances Chondrogenesis of Mesenchymal Stem Cells in vitro<br />Insert copy of Arthritis Research and Therapy pap...
In vitro models of cartilage as biomimetic systems for high-throughput screening of nutrient-derived compounds and combina...
Explant Culture<br />Advantages: <br />Chondrocytes remain phenotypically stable in their native matrix<br />Ideal for stu...
Curcumin and Resveratrol Counteract GAG Release in LPS Treated Cartilage Explants<br />
High-Throuoghput Proteomic Study of the Cartilage Secretome<br />
Commonly Identified Proteins:Canine Cartilage Secretome<br />Poster 121<br />Hillier et al.,<br />OARSI 2010<br />Proteins...
Commonly Identified Proteins:Equine Cartilage Secretome<br />Poster 503 Clutterbuck et al.,<br />OARSI 2010<br />Proteins ...
Western Blot Validation<br />Poster 503<br />Clutterbuck et al.,<br />OARSI 2010<br />
Heinegård D. (2009) Int J Exp Pathol. 90, 575-86<br />
Conclusions I<br />Whether supplements can be effectively and safely recommended to reduce NSAID usage is unclear and requ...
Conclusions II<br />There is potential for high quality basic research into gene nutrient interactions<br />However, subse...
A few words of caution…<br />
A few words of caution…<br />
Acknowledgements: Postgraduate Students and Funding<br />Abigail Clutterbuck<br />Adam Williams<br />Jasmine Penny<br />En...
Acknowledgements: Collaborators<br />Professor Alexandrina<br />Ferreira Mendes<br />Coimbra, Portugal<br />Professor Mehd...
Thank you for your attention<br />
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Oarsi 2010 Presentation A. Mobasheri

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Invited resentation given at the OARSI 2010 Congress - September 23-26 - Brussles, Belgium

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Oarsi 2010 Presentation A. Mobasheri

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

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