Fat and Osteoarthritis Tricia Ferguson & Parul Srivastav

“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 process these 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 time type 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 volume type 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. 2014; 53: 1-3. doi:10.1093/rheumatology/ket247 Herrero-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; 39:71-80. Available from: http://www.sciencedirect.com/science/article/pii/S0049017209000365 [Accessed 27th January 2014].

“White adipose tissue is not inert but metabolically active; it secretes a wide variety of adipokines.” LEPTIN RESISTIN OMENTIN LIPOCALIN 2 VASPIN ADIPONECTIN Important fact – do patients know this? CHEMERIN VISFATIN APELIN

Fat Adipokines Inflammation aka Adipose tissue Cytokines released from fat tissue – chemicals released from cells which are involved in inflammation Inflammation Damage

Studies which have linked metabolic syndrome to OA HTN → subchondral ischaemia → compromised nutrient exchange into articular cartilage → triggers bone remodelling → OA dyslipidaemia + deregulated cellular lipid metabolism in joint tissues → ectopic lipid deposition in chondrocytes → OA hyperglycaemia → local effects of oxidative stress and advanced glycation end-products → cartilage damage → OA hyperglycaemia → glucose accumulation → low-grade systemic inflammation → OA obesity-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 HTN Zhuo Q, Yang W, Chen J, Wang Y. Metabolic syndrome meets osteoarthritis. Nature Reviews Rheumatology. [Online] 2012; 8:729-37. Available from: http://www.nature.com/nrrheum/journal/v8/n12/full/nrrheum.2012.135.html [Accessed 29th January 2014].

Sample – Rheumatology Clinic – 27/01/14 Prevalence of Obesity Total Overweight/ Obese Other Rheum Conditions OA Other Co-morbidities Sex Age 28 22 RA, SLE, myositis, vasculitis, mechanical back pain, fibromyalgia, Sjogrens, other connective tissue diseases 11 (7- knees ) (4 - hands) All overweight High BP, T2DM, H.Pylori, Gynae complaints, F (17) M(5) 31-40: 2 41-50: 7 51-60: 7 61-70: 1 71+ : 5 Sample – Rheumatology Clinic – 27/01/14

Mrs ABC – 2014 65 year old lady Appointment for knee injection OA – both knees Obese Complaining of – pain, reduced ability to carry out daily activities, strain on family Trying to lose weight – personal trainer junk food

Obesity and OA Linked long time ago: 1988 – data from US National Health Survey Obese women  risk of OA X 4 Obese men  risk of OA X 5 Widely accepted theory of mechanical stress – can cause direct joint damage especially in weight bearing joints – knees Inhibition of cartilage matrix synthesis Pro-inflammatory factors: COX2, NO, PGE2, IL-1β However – 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 139.2 (1994): 119-129.

Leptin 16 kDa non-glycosylated peptide hormone LEP gene and ob gene (mice) Class 1 cytokine family Directly correlated with WAT mass

Leptin Dummon et al (2003): leptin levels in synovial fluid and cartilage in OA patients

Leptin – role in OA Chondrocytes 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 patients knee injection in rats – proteolytic enzymes and growth factors Higher levels in females – even when adjusted for BMI basic fibroblast growth factor (bFGF),

Effects of ↑ adiponectin...... ↑ NOS2 in chondrocytes NO inhibits collagen and proteoglycan synthesis, enhances apoptosis, and inhibits B1 integrin-dependent adhesion to the ECM ↑ IL-6 in chondrocytes Inhibits 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 processes Collagen type-2 degradation → Type-2 collagen neoepitope ↑ IL-6 in synovial fibroblasts Jikko 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. 1998; 22(9-10): 615-21. Amin A, Abramson S. The role of nitric oxide in articular cartilage breakdown in osteoarthritis. Current opinion in rheumatology. 1998; 10(3): 263-8.

Weight Loss and OA Numerous 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 symptoms Richette et al (2010) – 44 patients pre and post gastric surgery massive decrease in BMI (20%) Measurements : pain, function low-grade inflammation biomarkers of cartilage synthesis and degradation

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 weight Primary Care (weight loss) Specialist Care (+ drugs/ painkillers, injections, physio) Extreme Interventions (TKR, bariatric surgery etc.)

Many thanks to: Dr Bernie Colaço Prof Anthony Leeds Laura Paul

References Castañeda, S., Roman-Blas, J. A., Largo, R. & Herrero-Beaumont, G. What is osteoarthritis today? A progressive disease of changing phenotypes. Rheumatology (Oxford) (2014) 12-14. Knoop, Jesper, et al. "Identification of phenotypes with different clinical outcomes in knee osteoarthritis: data from the Osteoarthritis Initiative." Arthritis care & research 63.11 (2011): 1535-1542. Zhuo, Qi, et al. "Metabolic syndrome meets osteoarthritis." Nature Reviews Rheumatology 8.12 (2012): 729-737. Pottie, P., et al. "Obesity and osteoarthritis: more complex than predicted!." Annals of the rheumatic diseases 65.11 (2006): 1403-1405. Lago, Francisca, et al. "Adipokines as emerging mediators of immune response and inflammation." Nature clinical practice Rheumatology 3.12 (2007): 716-724. 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): 690-695. 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): 873-878. Dumond, Hélène, et al. "Evidence for a key role of leptin in osteoarthritis." Arthritis & Rheumatism 48.11 (2003): 3118-3129. 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): 700-707. Aspden, Richard M. "Obesity punches above its weight in osteoarthritis." Nature Reviews Rheumatology 7.1 (2010): 65-68.