Presentation on theme: "Fat and Osteoarthritis"— Presentation transcript:
1 Fat and Osteoarthritis Tricia Ferguson & Parul Srivastav
2 “OA is a heterogeneous syndrome” “Metabolic OA” another OA phenotype?“different clinical phenotypes that continuously evolve, eventually leading to common clinical manifestations”not forgetting that any co-morbidities will also modulate the OA processthese are not mutually exclusive - various OA tissue processes may overlap or become dominant at different stages of the disease, giving an evolving or varying clinical pattern between patients and also in the same patient over timetype I (genetically induced): susceptibility genes for OA and genes which determine disease progression and severity in an individual, genes which code for structural differences in ECM, and finally, genes which determine skeletal shape, bone mass density and cartilage volumetype II (oestrogen deficiency related): articular tissues are responsive to oestrogens, and oestrogen receptors are present in cartilage, bone, synovium, ligaments, and muscle. Furthermore, oestrogens influence the metabolism of articular tissues. Oestrogen deficiency is detrimental to cartilage homeostasis and subchondral bone turnover during OA development and progression. In addition, oestrogen deficiency is also often accompanied with an increase in fat mass, which in turn leads to increased levels of adipokines, particularly leptin, which has been shown to promote cartilage degradation type III (aging-related): changes in cartilage ECM (e.g. glycation end-product accumulation→ typeII collagen cross-linking→↓tensile strength and causes stiffness of cartilage) and also, decreased anabolic activity of chondrocytes therefore predominance of catabolic factors ensues = cartilage catabolism“Metabolic OA has recently been proposed as another OA phenotype and as a fifth component of the metabolic syndrome.”Castañeda S, Roman-Blas J, Largo R, Herrero-Beaumont G. Osteoarthritis: a progressive disease with changing phenotypes. Rheumatology ; 53: doi: /rheumatology/ket247Herrero-Beaumont G, Roman-Blas J, Castañeda S, Jimenez S. Primary osteoarthritis no longer primary: three subsets with distinct etiological, clinical, and therapeutic characteristics. Seminars in Arthritis and Rheumatism. [Online] 2009; 39: Available from: [Accessed 27th January 2014].
3 “White adipose tissue is not inert but metabolically active; it secretes a wide variety of adipokines.”LEPTINRESISTINOMENTINLIPOCALIN 2VASPINADIPONECTINImportant fact – do patients know this?CHEMERINVISFATINAPELIN
4 Fat Adipokines Inflammation aka Adipose tissue Cytokines released from fat tissue – chemicals released from cells which are involved in inflammationInflammationDamage
5 Studies which have linked metabolic syndrome to OA HTN → subchondral ischaemia → compromised nutrient exchange into articular cartilage → triggers bone remodelling → OAdyslipidaemia + deregulated cellular lipid metabolism in joint tissues → ectopic lipid deposition in chondrocytes → OAhyperglycaemia → local effects of oxidative stress and advanced glycation end-products → cartilage damage → OAhyperglycaemia → glucose accumulation → low-grade systemic inflammation → OAobesity-related metabolic factors (e.g. altered levels of adipokines) → induce expression of proinflammatory factors + degradative enzymes → inhibition of cartilage matrix synthesis → stimulation of subchondral bone remodelling → OA“metabolic OA is characterized by its major causative features—adipokines, hyperglycaemia and hormonal imbalance—and its targeting of mainly middle-aged people (45–65 years old), leading to knee OA, hand OA and a generalized osteoarthritic condition”metabolic syndrome = insulin resistance, visceral obesity, atherogenic dyslipidemia and HTNZhuo Q, Yang W, Chen J, Wang Y. Metabolic syndrome meets osteoarthritis. Nature Reviews Rheumatology. [Online] 2012; 8: Available from: [Accessed 29th January 2014].
9 Mrs ABC – 2014 65 year old lady Appointment for knee injection OA – both kneesObeseComplaining of – pain, reduced ability to carry out daily activities, strain on familyTrying to lose weight – personal trainerjunk food
10 Obesity and OALinked long time ago: 1988 – data from US National Health SurveyObese women risk of OA X 4Obese men risk of OA X 5Widely accepted theory of mechanical stress – can cause direct joint damage especially in weight bearing joints – kneesInhibition of cartilage matrix synthesisPro-inflammatory factors: COX2, NO, PGE2, IL-1βHowever – increased BMI associated with increased of OA in hands (Carman et al: prospective study with 23 year follow-up; n=1267)Carman, Wendy J., et al. "Obesity as a risk factor for osteoarthritis of the hand and wrist: a prospective study." American journal of epidemiology (1994):
11 Leptin 16 kDa non-glycosylated peptide hormone LEP gene and ob gene (mice)Class 1 cytokine familyDirectly correlated with WAT mass
13 LeptinDummon et al (2003): leptin levels in synovial fluid and cartilage in OA patients
14 Leptin – role in OAChondrocytes stimulated with leptin increased proliferation +synthesis of proteoglycans and collagen- Anabolic role in cartilage metabolism?Lots of contrary evidence for pro-inflammatory role:inflammatory markers (MMP-9 , MMP-13, NO, PGE2, IL-8)Higher level of leptin in OA patientsknee injection in rats – proteolytic enzymes and growth factorsHigher levels in females – even when adjusted for BMIbasic fibroblastgrowth factor (bFGF),
15 Effects of ↑ adiponectin...... ↑ NOS2 in chondrocytesNO inhibits collagen and proteoglycan synthesis, enhances apoptosis, and inhibits B1 integrin-dependent adhesion to the ECM↑ IL-6 in chondrocytesInhibits chondrocyte proliferation and depresses proteoglycan synthesis, enhances proteoglycan synthesis in combination with IL-1β↑ MMP-3 in chondrocytes↑ MMP-9 in chondrocytes↑ MCP-1 in chondrocytes↑ VCAM-1 in chondrocytes? Induction of chemotactic molecules → monocyte and leukocyte recruitment → ? cartilage-degrading processesCollagen type-2 degradation → Type-2 collagen neoepitope↑ IL-6 in synovial fibroblastsJikko A, Wakisaka T, Iwamoto M, Hiranuma H, Kato Y, Maeda T et al. Effects of interleukin-6 on proliferation and proteoglycan metabolism in articular chondrocyte cultures. Cell Biology International ; 22(9-10):Amin A, Abramson S. The role of nitric oxide in articular cartilage breakdown in osteoarthritis. Current opinion in rheumatology. 1998; 10(3):
16 Weight Loss and OANumerous studies have shown benefits of weight loss (Framingham and ADAPT studies)But is it just a mechanical difference or do adipokines play a role as well?Toda et al (1998) – weight loss programme in OA patients – loss of fat more important than weight reduction in reducing symptomsRichette et al (2010) – 44 patients pre and post gastric surgerymassive decrease in BMI (20%)Measurements : pain, functionlow-grade inflammationbiomarkers of cartilage synthesis and degradation
18 Summary Important to address the disease process at an earlier stage OA as reversible disease?? (MRI evidence of cartilage repair following weight loss)Management of clinical symptoms (chiefly pain) with reduction in either calories (Leeds) or fat % of body weightPrimary Care (weight loss)Specialist Care (+ drugs/ painkillers, injections, physio)Extreme Interventions(TKR, bariatric surgery etc.)
19 Many thanks to:Dr Bernie ColaçoProf Anthony LeedsLaura Paul
20 ReferencesCastañeda, S., Roman-Blas, J. A., Largo, R. & Herrero-Beaumont, G. What is osteoarthritis today? A progressive disease of changing phenotypes. Rheumatology (Oxford) (2014)Knoop, Jesper, et al. "Identification of phenotypes with different clinical outcomes in knee osteoarthritis: data from the Osteoarthritis Initiative." Arthritis care & research (2011):Zhuo, Qi, et al. "Metabolic syndrome meets osteoarthritis." Nature Reviews Rheumatology 8.12 (2012):Pottie, P., et al. "Obesity and osteoarthritis: more complex than predicted!." Annals of the rheumatic diseases (2006):Lago, Francisca, et al. "Adipokines as emerging mediators of immune response and inflammation." Nature clinical practice Rheumatology 3.12 (2007):Presle, N., et al. "Differential distribution of adipokines between serum and synovial fluid in patients with osteoarthritis. Contribution of joint tissues to their articular production." Osteoarthritis and Cartilage 14.7 (2006):Hu, Peng-fei, Jia-peng Bao, and Li-dong Wu. "The emerging role of adipokines in osteoarthritis: a narrative review." Molecular biology reports 38.2 (2011):Dumond, Hélène, et al. "Evidence for a key role of leptin in osteoarthritis." Arthritis & Rheumatism (2003):Berry, Patricia A., et al. "Temporal relationship between serum adipokines, biomarkers of bone and cartilage turnover, and cartilage volume loss in a population with clinical knee osteoarthritis." Arthritis & Rheumatism 63.3 (2011):Aspden, Richard M. "Obesity punches above its weight in osteoarthritis." Nature Reviews Rheumatology 7.1 (2010):