Abstract
Osteoarthritis (OA) is a most common multifactorial degenerative joint disease in elderly individuals. OA is affecting severely the quality of life of patients, while the causes of OA are not completely understood. Age, obesity, the female sex, and previous injury are considered as significant risk factors. Recently, increased levels of adipokines which are mainly produced by adipocytes have been detected in patients with osteoarthritis. Moreover, studies on different adipokines all reveal that they have played proinflammatory and catabolic/anabolic roles during the pathophysiology of OA. In the present review, we summarize current data on the effect of the adipose tissue-derived hormones leptin, adiponectin, resistin and visfatin on initiation and progression of OA.
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Felson DT, Chaisson CE, Hill CL, Totterman SM, Gale ME, Skinner KM, Kazis L, Gale DR (2001) The association of bone marrow lesions with pain in knee osteoarthritis. Ann Intern Med 134:541–549
Pottie P, Presle N, Terlain B, Netter P, Mainard D, Berenbaum F (2006) Obesity and osteoarthritis: more complex than predicted!. Ann Rheum Dis 65:1403–1405
Felson DT, Anderson JJ, Naimark A, Walker AM, Meenan RF (1988) Obesity and knee osteoarthritis. The Framingham Study. Ann Intern Med 109:18–24
Oliveria SA, Felson DT, Cirillo PA, Reed JI, Walker AM (1999) Body weight, body mass index, and incident symptomatic osteoarthritis of the hand, hip, and knee. Epidemiology 10:161–166
Christensen R, Bartels EM, Astrup A, Bliddal H (2007) Effect of weight reduction in obese patients diagnosed with knee osteoarthritis: a systematic review and meta-analysis. Ann Rheum Dis 66:433–439
Carman WJ, Sowers M, Hawthorne VM, Weissfeld LA (1994) Obesity as a risk factor for osteoarthritis of the hand and wrist: a prospective study. Am J Epidemiol 139:119–129
Kershaw EE, Flier JS (2004) Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 89:2548–2556
Rabe K, Lehrke M, Parhofer KG, Broedl UC (2008) Adipokines and insulin resistance. Mol Med 14:741–751
Gualillo O, Gonzalez-Juanatey JR, Lago F (2007) The emerging role of adipokines as mediators of cardiovascular function: physiologic and clinical perspectives. Trends Cardiovasc Med 17:275–283
Gabay O, Berenbaum F (2009) Adipokines in Arthritis: new kids on the block. Curr Rheumatol Rev 5:226–232
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432
Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Wool EA, Monroe CA, Tepper RI (1995) Identification and expression cloning of a leptin receptor, OB-R. Cell 83:1263–1271
Baumann H, Morella KK, White DW, Dembski M, Bailon PS, Kim H, Lai CF, Tartaglia LA (1996) The full-length leptin receptor has signaling capabilities of interleukin 6-type cytokine receptors. Proc Natl Acad Sci USA 93:8374–8378
Tong KM, Shieh DC, Chen CP, Tzeng CY, Wang SP, Huang KC, Chiu YC, Fong YC, Tang CH (2008) Leptin induces IL-8 expression via leptin receptor, IRS-1, PI3 K, Akt cascade and promotion of NF-kappaB/p300 binding in human synovial fibroblasts. Cell Signal 20:1478–1488
Tang CH, Lu DY, Yang RS, Tsai HY, Kao MC, Fu WM, Chen YF (2007) Leptin-induced IL-6 production is mediated by leptin receptor, insulin receptor substrate-1, phosphatidylinositol 3-kinase, Akt, NF-kappaB, and p300 pathway in microglia. J Immunol 179:1292–1302
Friedman JM, Halaas JL (1998) Leptin and the regulation of body weight in mammals. Nature 395:763–770
Faggioni R, Feingold KR, Grunfeld C (2001) Leptin regulation of the immune response and the immunodeficiency of malnutrition. FASEB J 15:2565–2571
Siegmund B, Sennello JA, Jones-Carson J, Gamboni-Robertson F, Lehr HA, Batra A, Fedke I, Zeitz M, Fantuzzi G (2004) Leptin receptor expression on T lymphocytes modulates chronic intestinal inflammation in mice. Gut 53:965–972
Bokarewa M, Bokarew D, Hultgren O, Tarkowski A (2003) Leptin consumption in the inflamed joints of patients with rheumatoid arthritis. Ann Rheum Dis 62:952–956
Figenschau Y, Knutsen G, Shahazeydi S, Johansen O, Sveinbjornsson B (2001) Human articular chondrocytes express functional leptin receptors. Biochem Biophys Res Commun 287:190–197
Dumond H, Presle N, Terlain B, Mainard D, Loeuille D, Netter P, Pottie P (2003) Evidence for a key role of leptin in osteoarthritis. Arthritis Rheum 48:3118–3129
Nakajima R, Inada H, Koike T, Yamano T (2003) Effects of leptin to cultured growth plate chondrocytes. Horm Res 60:91–98
Blanco FJ, Guitian R, Vazquez-Martul E, de Toro FJ, Galdo F (1998) Osteoarthritis chondrocytes die by apoptosis A possible pathway for osteoarthritis pathology. Arthritis Rheum 41:284–289
Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L (1994) Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med 331:889–895
Simopoulou T, Malizos KN, Iliopoulos D, Stefanou N, Papatheodorou L, Ioannou M, Tsezou A (2007) Differential expression of leptin and leptin’s receptor isoform (Ob-Rb) mRNA between advanced and minimally affected osteoarthritic cartilage; effect on cartilage metabolism. Osteoarthritis Cartilage 15:872–883
Ku JH, Lee CK, Joo BS, An BM, Choi SH, Wang TH, Cho HL (2009) Correlation of synovial fluid leptin concentrations with the severity of osteoarthritis. Clin Rheumatol 28:1431–1435
Vuolteenaho K, Koskinen A, Kukkonen M, Nieminen R, Paivarinta U, Moilanen T, Moilanen E (2009) Leptin enhances synthesis of proinflammatory mediators in human osteoarthritic cartilage-mediator role of NO in leptin-induced PGE2, IL-6, and IL-8 production. Mediators Inflamm 2009:345838
Iliopoulos D, Malizos KN, Tsezou A (2007) Epigenetic regulation of leptin affects MMP-13 expression in osteoarthritic chondrocytes: possible molecular target for osteoarthritis therapeutic intervention. Ann Rheum Dis 66:1616–1621
Otero M, Lago R, Lago F, Reino JJ, Gualillo O (2005) Signalling pathway involved in nitric oxide synthase type II activation in chondrocytes: synergistic effect of leptin with interleukin-1. Arthritis Res Ther 7:R581–R591
Griffin TM, Huebner JL, Kraus VB, Guilak F (2009) Extreme obesity due to impaired leptin signaling in mice does not cause knee osteoarthritis. Arthritis Rheum 60:2935–2944
Thirunavukkarasu K, Pei Y, Wei T (2007) Characterization of the human ADAMTS-5 (aggrecanase-2) gene promoter. Mol Biol Rep 34:225–231
Malfait AM, Liu RQ, Ijiri K, Komiya S, Tortorella MD (2002) Inhibition of ADAM-TS4 and ADAM-TS5 prevents aggrecan degradation in osteoarthritic cartilage. J Biol Chem 277:22201–22208
Huang K, Wu LD (2010) Suppression of aggrecanase: a novel protective mechanism of dehydroepiandrosterone in osteoarthritis? Mol Biol Rep 37:1241–1245
Bao JP, Chen WP, Feng J, Hu PF, Shi ZL, Wu LD (2009) Leptin plays a catabolic role on articular cartilage. Mol Biol Rep. doi:10.1007/s11033-009-9911-x
Morroni M, De Matteis R, Palumbo C, Ferretti M, Villa I, Rubinacci A, Cinti S, Marotti G (2004) In vivo leptin expression in cartilage and bone cells of growing rats and adult humans. J Anat 205:291–296
Reseland JE, Syversen U, Bakke I, Qvigstad G, Eide LG, Hjertner O, Gordeladze JO, Drevon CA (2001) Leptin is expressed in and secreted from primary cultures of human osteoblasts and promotes bone mineralization. J Bone Miner Res 16:1426–1433
Zhao CQ, Liu D, Li H, Jiang LS, Dai LY (2008) Expression of leptin and its functional receptor on disc cells: contribution to cell proliferation. Spine (Phila Pa 1976) 33:E858–864
Lee YJ, Park JH, Ju SK, You KH, Ko JS, Kim HM (2002) Leptin receptor isoform expression in rat osteoblasts and their functional analysis. FEBS Lett 528:43–47
Reseland JE, Gordeladze JO (2002) Role of leptin in bone growth: central player or peripheral supporter? FEBS Lett 528:40–42
Mutabaruka MS, Aoulad Aissa M, Delalandre A, Lavigne M, Lajeunesse D (2010) Local leptin production in osteoarthritis subchondral osteoblasts may be responsible for their abnormal phenotypic expression. Arthritis Res Ther 12:R20
Presle N, Pottie P, Dumond H, Guillaume C, Lapicque F, Pallu S, Mainard D, Netter P, Terlain B (2006) Differential distribution of adipokines between serum and synovial fluid in patients with osteoarthritis. Contribution of joint tissues to their articular production. Osteoarthritis Cartilage 14:690–695
Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF (1995) A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 270:26746–26749
Hu E, Liang P, Spiegelman BM (1996) AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem 271:10697–10703
Pajvani UB, Du X, Combs TP, Berg AH, Rajala MW, Schulthess T, Engel J, Brownlee M, Scherer PE (2003) Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications fpr metabolic regulation and bioactivity. J Biol Chem 278:9073–9085
Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T, Miyagishi M, Hara K, Tsunoda M, Murakami K, Ohteki T, Uchida S, Takekawa S, Waki H, Tsuno NH, Shibata Y, Terauchi Y, Froguel P, Tobe K, Koyasu S, Taira K, Kitamura T, Shimizu T, Nagai R, Kadowaki T (2003) Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423:762–769
Tang CH, Chiu YC, Tan TW, Yang RS, Fu WM (2007) Adiponectin enhances IL-6 production in human synovial fibroblast via an AdipoR1 receptor, AMPK, p38, and NF-kappa B pathway. J Immunol 179:5483–5492
Tilg H, Kaser A (2009) Adiponectin and JNK: metabolic/inflammatory pathways affecting gastrointestinal carcinogenesis. Gut 58:1576–1577
Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA (2001) Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86:1930–1935
Funahashi T, Nakamura T, Shimomura I, Maeda K, Kuriyama H, Takahashi M, Arita Y, Kihara S, Matsuzawa Y (1999) Role of adipocytokines on the pathogenesis of atherosclerosis in visceral obesity. Intern Med 38:202–206
Gilardini L, McTernan PG, Girola A, da Silva NF, Alberti L, Kumar S, Invitti C (2006) Adiponectin is a candidate marker of metabolic syndrome in obese children and adolescents. Atherosclerosis 189:401–407
Bruun JM, Lihn AS, Verdich C, Pedersen SB, Toubro S, Astrup A, Richelsen B (2003) Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro investigations in humans. Am J Physiol Endocrinol Metab 285:E527–E533
Fasshauer M, Kralisch S, Klier M, Lossner U, Bluher M, Klein J, Paschke R (2003) Adiponectin gene expression and secretion is inhibited by interleukin-6 in 3T3-L1 adipocytes. Biochem Biophys Res Commun 301:1045–1050
Engeli S, Feldpausch M, Gorzelniak K, Hartwig F, Heintze U, Janke J, Mohlig M, Pfeiffer AF, Luft FC, Sharma AM (2003) Association between adiponectin and mediators of inflammation in obese women. Diabetes 52:942–947
Otero M, Lago R, Gomez R, Lago F, Dieguez C, Gomez-Reino JJ, Gualillo O (2006) Changes in plasma levels of fat-derived hormones adiponectin, leptin, resistin and visfatin in patients with rheumatoid arthritis. Ann Rheum Dis 65:1198–1201
Ehling A, Schaffler A, Herfarth H, Tarner IH, Anders S, Distler O, Paul G, Distler J, Gay S, Scholmerich J, Neumann E, Muller-Ladner U (2006) The potential of adiponectin in driving arthritis. J Immunol 176:4468–4478
Chen TH, Chen L, Hsieh MS, Chang CP, Chou DT, Tsai SH (2006) Evidence for a protective role for adiponectin in osteoarthritis. Biochim Biophys Acta 1762:711–718
Uchida K, Urabe K, Naruse K, Ogawa Z, Mabuchi K, Itoman M (2009) Hyperlipidemia and hyperinsulinemia in the spontaneous osteoarthritis mouse model, STR/Ort. Exp Anim 58:181–187
Lago R, Gomez R, Otero M, Lago F, Gallego R, Dieguez C, Gomez-Reino JJ, Gualillo O (2008) A new player in cartilage homeostasis: adiponectin induces nitric oxide synthase type II and pro-inflammatory cytokines in chondrocytes. Osteoarthritis Cartilage 16:1101–1109
Filkova M, Liskova M, Hulejova H, Haluzik M, Gatterova J, Pavelkova A, Pavelka K, Gay S, Muller-Ladner U, Senolt L (2009) Increased serum adiponectin levels in female patients with erosive compared with non-erosive osteoarthritis. Ann Rheum Dis 68:295–296
Choi HM, Lee YA, Lee SH, Hong SJ, Hahm DH, Choi SY, Yang HI, Yoo MC, Kim KS (2009) Adiponectin may contribute to synovitis and joint destruction in rheumatoid arthritis by stimulating vascular endothelial growth factor, matrix metalloproteinase-1, and matrix metalloproteinase-13 expression in fibroblast-like synoviocytes more than proinflammatory mediators. Arthritis Res Ther 11:R161
Steppan CM, Brown EJ, Wright CM, Bhat S, Banerjee RR, Dai CY, Enders GH, Silberg DG, Wen X, Wu GD, Lazar MA (2001) A family of tissue-specific resistin-like molecules. Proc Natl Acad Sci USA 98:502–506
Patel L, Buckels AC, Kinghorn IJ, Murdock PR, Holbrook JD, Plumpton C, Macphee CH, Smith SA (2003) Resistin is expressed in human macrophages and directly regulated by PPAR gamma activators. Biochem Biophys Res Commun 300:472–476
Savage DB, Sewter CP, Klenk ES, Segal DG, Vidal-Puig A, Considine RV, O’Rahilly S (2001) Resistin/Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans. Diabetes 50:2199–2202
Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA (2001) The hormone resistin links obesity to diabetes. Nature 409:307–312
Senolt L, Housa D, Vernerova Z, Jirasek T, Svobodova R, Veigl D, Anderlova K, Muller-Ladner U, Pavelka K, Haluzik M (2007) Resistin in rheumatoid arthritis synovial tissue, synovial fluid and serum. Ann Rheum Dis 66:458–463
Rajala MW, Qi Y, Patel HR, Takahashi N, Banerjee R, Pajvani UB, Sinha MK, Gingerich RL, Scherer PE, Ahima RS (2004) Regulation of resistin expression and circulating levels in obesity, diabetes, and fasting. Diabetes 53:1671–1679
Silswal N, Singh AK, Aruna B, Mukhopadhyay S, Ghosh S, Ehtesham NZ (2005) Human resistin stimulates the pro-inflammatory cytokines TNF-alpha and IL-12 in macrophages by NF-kappaB-dependent pathway. Biochem Biophys Res Commun 334:1092–1101
Kaser S, Kaser A, Sandhofer A, Ebenbichler CF, Tilg H, Patsch JR (2003) Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro. Biochem Biophys Res Commun 309:286–290
Bokarewa M, Nagaev I, Dahlberg L, Smith U, Tarkowski A (2005) Resistin, an adipokine with potent proinflammatory properties. J Immunol 174:5789–5795
Lee JH, Ort T, Ma K, Picha K, Carton J, Marsters PA, Lohmander LS, Baribaud F, Song XY, Blake S (2009) Resistin is elevated following traumatic joint injury and causes matrix degradation and release of inflammatory cytokines from articular cartilage in vitro. Osteoarthritis Cartilage 17:613–620
Samal B, Sun Y, Stearns G, Xie C, Suggs S, McNiece I (1994) Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor. Mol Cell Biol 14:1431–1437
Brown JE, Onyango DJ, Ramanjaneya M, Conner AC, Patel ST, Dunmore SJ, Randeva HS (2010) Visfatin regulates insulin secretion, insulin receptor signalling and mRNA expression of diabetes-related genes in mouse pancreatic beta-cells. J Mol Endocrinol 44:171–178
Revollo JR, Korner A, Mills KF, Satoh A, Wang T, Garten A, Dasgupta B, Sasaki Y, Wolberger C, Townsend RR, Milbrandt J, Kiess W, Imai S (2007) Nampt/PBEF/Visfatin regulates insulin secretion in beta cells as a systemic NAD biosynthetic enzyme. Cell Metab 6:363–375
Dahl TB, Yndestad A, Skjelland M, Oie E, Dahl A, Michelsen A, Damas JK, Tunheim SH, Ueland T, Smith C, Bendz B, Tonstad S, Gullestad L, Froland SS, Krohg-Sorensen K, Russell D, Aukrust P, Halvorsen B (2007) Increased expression of visfatin in macrophages of human unstable carotid and coronary atherosclerosis: possible role in inflammation and plaque destabilization. Circulation 115:972–980
Jia SH, Li Y, Parodo J, Kapus A, Fan L, Rotstein OD, Marshall JC (2004) Pre-B cell colony-enhancing factor inhibits neutrophil apoptosis in experimental inflammation and clinical sepsis. J Clin Invest 113:1318–1327
Moschen AR, Kaser A, Enrich B, Mosheimer B, Theurl M, Niederegger H, Tilg H (2007) Visfatin, an adipocytokine with proinflammatory and immunomodulating properties. J Immunol 178:1748–1758
Brentano F, Schorr O, Ospelt C, Stanczyk J, Gay RE, Gay S, Kyburz D (2007) Pre-B cell colony-enhancing factor/visfatin, a new marker of inflammation in rheumatoid arthritis with proinflammatory and matrix-degrading activities. Arthritis Rheum 56:2829–2839
Nowell MA, Richards PJ, Fielding CA, Ognjanovic S, Topley N, Williams AS, Bryant-Greenwood G, Jones SA (2006) Regulation of pre-B cell colony-enhancing factor by STAT-3-dependent interleukin-6 trans-signaling: implications in the pathogenesis of rheumatoid arthritis. Arthritis Rheum 54:2084–2095
Gosset M, Berenbaum F, Salvat C, Sautet A, Pigenet A, Tahiri K, Jacques C (2008) Crucial role of visfatin/pre-B cell colony-enhancing factor in matrix degradation and prostaglandin E2 synthesis in chondrocytes: possible influence on osteoarthritis. Arthritis Rheum 58:1399–1409
Senolt L, Polanska M, Filkova M, Oslejskova L, Pavelka K, Gay S, Haluzik M, Vencovsky J (2009) Vaspin and omentin: new adipokines differentially regulated at the site of inflammation in rheumatoid arthritis. Ann Rheum Dis. doi:10.1136/ard.2009.119735
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This work was supported by grants from Health Bureau of Zhejiang Province (2006A055).
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Hu, Pf., Bao, Jp. & Wu, Ld. The emerging role of adipokines in osteoarthritis: a narrative review. Mol Biol Rep 38, 873–878 (2011). https://doi.org/10.1007/s11033-010-0179-y
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DOI: https://doi.org/10.1007/s11033-010-0179-y