The role of metabolic syndrome in the pathogenesis of knee osteoarthritis: a new view on the problem

 Currently, numerous studies undeniably prove the influence of metabolic syndrome on osteoarthritis (OA) progression.
In hyperlipidemia, free fatty acids abnormally accumulate in the cartilage tissue and provoke cell dysfunction and necrosis. Studies show that palmitate and stearate have a pronounced proapoptotic effect on chondrocytes of the articular cartilage.
Mediators of the systemic inflammatory response produced by the adipose tissue act as a significant link in the pathogenesis of metabolic OA in the knee joint. Metabolic disorders, insulin resistance, and dyslipidemia 
boost production of inflammatory mediators and glycosylated compounds and formation of free oxygen radicals provoking endothelial dysfunction.
A relationship between intra-articular structures (articular cartilage, synovial membrane, subchondral bone and synovial fluid) and the intra-articular infrapatellar fat pad is a local pathogenetic factor in the metabolic OA of
the knee. It is proven that the intra-articular infrapatellar fat pad increases significantly in obese patients. Due to proximity to the articular cartilage and synovial membrane, the adipose tissue is in close contact with them. 
The influence of systemic metabolites activates the growth of adipocytes, preadipocytes, macrophages, fibroblasts, and other fat body cells which enhance the production and release of adipokines, such as leptin, adiponectin, visfatin, and cytokines, that in turn stimulate aseptic inflammation resulting in development of synovitis, cartilage degeneration, and gonarthrosis progression.
Therefore, the metabolic syndrome has a negative impact on the condition of the joint tissues, contributing to the development of gonarthrosis or its progression. It manifests itself both through systemic effects and the local impact of the hypertrophied infrapatellar fat pad on the components of the synovial joint environment. 

1. Лутов Ю.В., Селятицкая В.Г., Васильева О.В., Пинхасов Б.Б. Взаимоотношения основных факторов патогенеза метаболического синдрома с его компонентами у мужчин. Сибирский научный медицинский журнал. 2017; 37 (6): 97–104.

2. Lementowski P.W., Zelicof S.B. Obesity and osteoarthritis. Am. J. Orthop. (Belle Mead. NJ). 2008; 37 (3): 148–151.

3. De Oliveira N.C., Alfieri F.M., Lima A.R.S., Portes L.A. Lifestyle and pain in women with knee osteoarthritis. Am. J. Lifestyle Med. 2019; 13 (6): 606–610. DOI: 10.1177/1559827617722112.

4. Корочина К.В., Чернышева Т.В., Корочина И.Э., Полякова В.С., Шамаев С.Ю. Ранние морфофункциональные преобразования суставного хряща крыс с экспериментальным остеоартрозом различного генеза. Бюллетень экспериментальной биологии и медицины. 2018; 165 (4): 494–499.

5. Otero M., Lago R., Gomez R. et al. Changes in plasma levels of fat-derived hormones adiponectin, leptin, resistin and visfatin in patients with rheumatoid arthritis. Ann. Rheum. Dis. 2006; 65 (9): 1198–1201. DOI: 10.1136/ard.2005.046540.

6. Reid J.L., Morton D.J., Wingard D.L., Garrett M.D., von Muhlen D., Slymen D. Obesity and other cardiovascular disease risk factors and their association with osteoarthritis in Southern California American Indians, 2002–2006. Ethn. Dis. 2010; 20 (4): 416–422.

7. Шостак Н.А. Остеоартроз – современные подходы к диагностике и лечению. РМЖ. 2003; 14: 803.

8. Patsch J.M., Kiefer F.W., Varga P., Pail P., Rauner M., Stupphann D. et al. Increased bone resorption and impaired bone microarchitecture in short-term and extended high-fat diet-induced obesity. Metabolism. 2011; 60 (2): 243–249. DOI: 10.1016/j.metabol.2009.11.023.

9. Alfieri F.M., Silva N., Battistella L.R. Study of the relation between body weight and functional limitations and pain in patients with knee osteoarthritis. Einstein. 2017; 15 (3): 307–312. DOI: 10.1590/S1679-45082017AO4082.

10. Losina E., Walensky R.P., Reichmann W.M., Holt H.L., Gerlovin H., Solomon D.H., Jordan J.M., Hunter D.J., Suter L.G., Weinstein A.M., Paltiel A.D., Katz J.N. Impact of obesity and knee osteoarthritis on morbidity and mortality in older Americans. Ann. Intern. Med. 2011; 154 (4): 217–226. DOI: 10.7326/0003-4819-154-4-201102150-00001.

11. Felson D.T., Anderson J.J., Naimark A., Walker A.M. Meenan R.F. Obesity and knee osteoarthritis. The Framingham Study. Annals of Internal Medicine. 1988; 109 (1): 18–24. DOI: 10.7326/0003-4819-109-1-18.

12. Grotle M., Hagen K.B., Natvig B., Dahl F.A., Kvien T.K. Obesity and osteoarthritis in knee, hip and/or hand: an epidemiological study in the general population with 10 years follow-up. BMC Musculoskelet. Disord. 2008; 9: 132. DOI: 10.1186/1471-2474-9-132.

13. Fingleton C., Smart K., Moloney N., Fullen B. M., Doody C. Pain sensitization in people with knee osteoarthritis: a systematic review and meta-analysis. Osteoarthr. Cartil. 2015; 23 (7): 1043–1056. DOI: 10.1016/j.joca.2015.02.163.

14. Goldring M.B., Otero M. Inflammation in osteoarthritis. Curr. Opin. Rheumatol. 2011; 23 (5): 471–478. DOI: 10.1097/BOR.0b013e328349c2b1.

15. Губская Е.Ю., Кузьминец А.А., Гуцул В.Н., Лавренчук И.О. Кишечный микробиом и остеоартрит. Гастроэнтерология. 2019; 53 (2): 132–137. DOI: 10.22141/2308-2097.53.2. 2019.168988.

16. Boutagy N.E., McMillan R.P., Frisard M.I., Hulver M.V. Metabolic endotoxemia with obesity: Is it real and is it relevant? Biochimie. 2016; 124: 11–20. DOI: 10.1016/j.biochi.2015.06.020.

17. Bobacz K., Sunk I.G., Hofstaetter J.G., Amoyo L., Toma C.D., Akira S., Weichhart T., Saemann M., Smolen J.S. Toll-like receptors and chondrocytes: the lipopolysaccharide-induced decrease in cartilage matrix synthesis is dependent on the presence of toll-like receptor 4 and antagonized by bone morphogenetic protein 7. Arthritis Rheum. 2007; 56 (6): 1880–1893. DOI: 10.1002/art.22637.

18. Fatkhullina A.R. AniInterleukin-23-interleukin-22 axis regulates intestinal microbial homeostasis to protect from diet-induced atherosclerosis. Immunity. 2018; 49 (5): 943– 957. DOI: 10.1016/j.immuni.2018.09.011.

19. Lee S.W., Rho J.H., Lee S.Y., Chung W.T., Oh Y.J., Kim J.H., Yoo S.H., Kwon W.Y., Bae J.Y., Seo S.Y., Sun H., Kim H.Y., Yoo Y.H. Dietary fat-associated osteoarthritic chondrocytes gain resistance to lipotoxicity through PKCK2/STAMP2/FSP27. Bone Res. 2018; 6: 20. DOI: 10.1038/s41413-018-0020-0.

20. Simopoulos A.P. Importance of the omega-6/omega-3 balance in health and disease: evolutionary aspects of diet. World Rev. Nutr. Diet. 2011; 102: 10–21. DOI: 10.1159/000327785.

21. Calder P.C. Omega-3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology? Br. J. Clin. Pharmacol. 2013; 75 (3): 645–662. DOI: 10.1111/j.1365-2125.2012.04374.x.

22. Courties A., Gualillo O., Berenbaum F., Sellam J. Metabolic stress-induced joint inflammation and osteoarthritis. Osteoarthritis Cartilage. 2015; 23 (11): 1955–1965. DOI: 10.1016/j.joca.2015.05.016.

23. Yang H., Jin X., Kei Lam C.W., Yan S.K. Oxidative stress and diabetes mellitus. Clin. Chem. Lab. Med. 2011; 49 (11): 1773–1782. DOI: 10.1515/CCLM.2011.250.

24. Омельяненко Н.П., Слуцкий Л.И. Соединительная ткань: (Гистофизиология и биохимия); под ред. С.П. Миронова: В 2 т., т. 1. М.: Известия, 2009: 14–17.

25. Захватов А.Н., Козлов С.А., Аткина Н.А., Дудоров И.И. Динамика уровня цитокинов при экспериментальном посттравматическом артрите. Медицинская иммунология. 2016; 18 (1): 91–96. DOI: 10.15789/1563-0625-2016-1-91-96.

26. Алексеева Л.И. Новые представления о патогенезе остеоартрита, роль метаболических нарушений. Ожирение и метаболизм. 2019; 16 (2): 75–82. DOI: 10.14341/omet10274.

27. Mutabaruka M.S., Aissa M.A., Delalandre A. et al. Local leptin production in osteoarthritis subchondral osteoblasts may be responsible for their abnormal phenotypic expression. Arthritis Res. Ther. 2010; 12 (1): R20. DOI: 10.1186/ar2925.

28. Dixit V., Yang H., Cooper-Jenkins A. et al. Reduction of T cell-derived ghrelin enhances proinflammatory cytokine expression: implications for age-associated increases in inflammation. Blood. 2009; 113: 5202–5205.

29. Matarese G., Moschos S., Mantzoros C.S. Leptin in immunology. J. Immunol. 2005; 174: 3137–3142.

30. Yang W.H., Liu S.C., Tsai C.H. et al. Leptin induces IL- 6 expression through OBRl receptor signaling pathway in human synovial fibroblasts. PLoS One. 2013; 8 (9): e75551. DOI: 10.1371/journal.pone.0075551.

31. Sasaki K., Hattori T., Fujisawa T. et al. Nitric oxide mediates interleukin-1-induced gene expression of matrix metalloproteinases and basic fibroblast growth factor in cultured rabbit articular chondrocytes. J. Biochem. 1998; 123: 431–439.

32. Bao J.P., Chen W.P., Feng J. et al. Leptin plays a catabolic role on articular cartilage. Mol. Biol. Rep. 2010; 37 (7): 3265–3272. DOI: 10.1007/s11033-009-9911-x.

33. Conde J., Scotece M., Lopez V. et al. Adiponectin and leptin induce VCAM-1 expression in human and murine chondrocytes. PLoS One. 2012; 7 (12): e52533. DOI: 10.1371/journal.pone.0052533.

34. Giles J.T., van der Heijde D.M, Bathon J.M. Association of circulating adiponectin levels with progression of radiographic joint destruction in rheumatoid arthritis. Ann. Rheum. Dis. 2009; 70 (9): 1562–1568. DOI: 10.1136/ard.2011.150813.

35. Scotece M., Conde J., Lopez V. et al. Adiponectin and leptin: new targets in inflammation. Basic Clin. Pharmacol. Toxicol. 2014; 114 (1): 97–102. DOI: 10.1111/bcpt.12109.

36. Gosset M., Berenbaum F., Salvat C., Sautet A., Pigenet A., Tahiri K., Jacques C. Crucial role of visfatin/pre-B cell colony-enhancing factor in matrix degradation and prostaglandin E 2 synthesis in chondrocytes: possible influence on osteoarthritis. Arthritis Rheum. 2008; 58 (5): 1399–1409. DOI: 10.1002/art.23431.

37. Moschen A.R., Kaser A., Enrich B., Mosheimer B., Theurl M., Niederegger H., Tilg H. Visfatin, an adipocytokine with proinflammatory and immunomodulating properties. J. Immunol. 2007; 178 (3): 1748–1758. DOI: 10.4049/jimmunol.178.3.1748.

38. Jacques C., Holzenberger M., Mladenovic Z., Salvat C., Pecchi E., Berenbaum F., Gosset M. Proinflammatory actions of visfatin/nicotinamide phosphoribosyltransferase (Nampt) involve regulation of insulin signaling pathway and Nampt enzymatic activity. J. Biol. Chem. 2012; 287 (18): 15100–15108. DOI: 10.1074/jbc.M112.350215.

39. Poulet B., Staines K.A. New developments in osteoarthritis and cartilage biology. Curr. Opin. Pharmacol. 2016; 28: 8–13. DOI: 10.1016/j.coph.2016.02.009.

40. Cheleschi S., Gallo I., Barbarino M., Giannotti S., Mondanelli N., Giordano A., Tenti S., Fioravanti A. MicroRNA Mediate Visfatin and Resistin Induction of Oxidative Stress in Human Osteoarthritic Synovial Fibroblasts Via NF-κB Pathway. Int. J. Mol. Sci. 2019; 20 (20): 5200. DOI: 10.3390/ijms20205200.

41. Del Rey M.J, Valín А., Usategui A., Ergueta S., Martín E., Municio C., Cañete J.D, Blanco F.J, Criado G., Pablos J.L. Senescent synovial fibroblasts accumulate prematurely in rheumatoid arthritis tissues and display an enhanced inflammatory phenotype. Immun. Ageing. 2019; 16: 29. DOI: 10.1186/s12979-019-0169-4.

42. Wang Y., Xu J., Zhang X., Wang C., Huang Y., Dai K., Zhang X. TNF-α-induced LRG1 promotes angiogenesis and mesenchymal stem cell migration in the subchondral bone during osteoarthritis. Cell Death Dis. 2017; 8 (3): e2715. DOI: 10.1038/cddis.2017.129.

43. Kusumbe A.P., Ramasamy S.K., Adams R.H. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature. 2014; 507 (7492): 323–328. DOI: 10.1038/nature13145.

44. Кабалык М.А., Невзорова В.А. Дислипидемия и атеросклероз в патогенезе остеоартрита. Медицинский альманах. 2018; 56 (5): 220–224. DOI: 10.21145/2499-9954-2018-5-220-224.

45. Hunter D.J., Felson D.T. Osteoarthritis. BMJ. 2006; 332 (7542): 639–642. DOI: 10.1136/bmj.332.7542.639.

46. Pan F., Han W., Wang X., Liu Z., Jin X., Antony B., Cicuttini F., Jones G., Ding C. A longitudinal study of the association between infrapatellar fat pad maximal area and changes in knee symptoms and structure in older adults. Ann. Rheum. Dis. 2015; 74 (10): 1818–1824. DOI: 10.1136/annrheumdis-2013-205108.

47. Ding C., Stannus O., Cicuttini F., Antony B., Jones G. Body fat is associated with increased and lean mass with decreased knee cartilage loss in older adults: a prospective cohort study. Int. J. Obes. (Lond). 2013; 37 (6): 822–827. DOI: 10.1038/ijo.2012.136.

48. Dumond H., Presle N., Terlain B., Mainard D., Loeuille D., Netter P., Pottie P. Evidence for a key role of leptin in osteoarthritis. Arthritis Rheum. 2003; 48 (11): 3118–3129. DOI: 10.1002/art.11303.

49. Xie J., Huang Z., Yu X., Zhou L., Pei F. Clinical implications of macrophage dysfunction in the development of osteoarthritis of the knee. Cytokine Growth Factor Rev. 2019; 46: 36–44. DOI: 10.1016/j.cytogfr.2019.03.004.

50. Beekhuizen M., Gierman L.M., van Spil W.E., Van Osch G.J., Huizinga T.W., Saris D.B., Creemers L.B., Zuurmond A.M. An explorative study comparing levels of soluble mediators in control and osteoarthritic synovial fluid. Osteoarthritis Cartilage. 2013; 21 (7): 918–922. DOI: 10.1016/j.joca.2013.04.002.

51. Witoński D., Wągrowska-Danilewicz M., Kęska R., Raczyńska-Witońska G., Stasikowska-Kanicka O. Increased interleukin 6 and tumour necrosis factor α expression in the infrapatellar fat pad of the knee joint with the anterior knee pain syndrome: a preliminary report. Pol. J. Pathol. 2010; 61 (4): 213–218.

52. Ballegaard C., Riis R.G.C., Bliddal H., Christensen R., Henriksen M., Bartels E.M. et al. Knee pain and inflammation in the infrapatellar fat pad estimated by conventional and dynamic contrast-enhanced magnetic resonance imaging in obese patients with osteoarthritis: a cross-sectional study. Osteoarthritis Cartilage. 2014; 22 (7): 933–940. DOI: 10.1016/j.joca.2014.04.018.

53. Eitner A., Hofmann G.O., Schaible H.G. Mechanisms of оsteoarthritic Pain. Studies in Humans and Experimental Models. Front. Mol. Neurosci. 2017; 10: 349. DOI: 10.3389/fnmol.2017.00349.

54. Cowan S.M., Hart H.F., Warden S.J., Crossley K.M. Infrapatellar fat pad volume is greater in individuals with patellofemoral joint osteoarthritis and associated with pain. Rheumatol. Int. 2015; 35 (8): 1439–1442. DOI: 10.1007/s00296-015-3250-0.

55. Wang B., Lang Y., Zhang L. Histopathological changes in the infrapatellar fat pad in an experimental rabbit model of early patellofemoral osteoarthritis. Knee. 2019; 26 (1): 2–13. DOI: 10.1016/j.knee.2018.06.010.