Serum levels of leptin and high molecular weight adiponectin are inversely associated with radiographic spinal progression in patients with ankylosing spondylitis: results from the ENRADAS trial

Agnes Hartl, Joachim Sieper, Uta Syrbe, Joachim Listing, Kay-Geert Hermann, Martin Rudwaleit, Denis Poddubnyy, Agnes Hartl, Joachim Sieper, Uta Syrbe, Joachim Listing, Kay-Geert Hermann, Martin Rudwaleit, Denis Poddubnyy

Abstract

Background: Previous research indicates a role of adipokines in inflammation and osteogenesis. Hence adipokines might also have a pathophysiological role in inflammation and new bone formation in patients with ankylosing spondylitis (AS). The aim of this study was to investigate the role of adipokine serum levels as predictors of radiographic spinal progression in patients with AS.

Methods: A total of 120 patients with definite AS who completed a 2-year follow up in the ENRADAS trial were included in the current study. Radiographic spinal progression was defined as: (1) worsening of the modified Stoke Ankylosing Spondylitis spine (mSASSS) score by ≥2 points and/or (2) new syndesmophyte formation or progression of existing syndesmophytes after 2 years. Serum levels of adipokines (adiponectin (APN) and its high molecular weight form (HMW-APN), chemerin, leptin, lipocalin-2, omentin, resistin, visfatin) were measured using enzyme-linked immunosorbent assays.

Results: There was a significant association between radiographic spinal progression and both leptin and HMW-APN. Baseline serum levels of both adipokines were lower in patients who showed radiographic spinal progression after 2 years. This association was especially evident in men; they had generally lower leptin and HMW-APN serum levels as compared to women. The inverse association between adipokines and radiographic spinal progression was confirmed in the logistic regression analysis: the odds ratios (OR) for the outcome "no mSASSS progression ≥2 points" were 1.16 (95% CI 1.03 to 1.29) and 1.17 (95% CI 0.99 to 1.38), for leptin and HMW-APN, respectively; for "no syndesmophyte formation/progression" the respective OR were 1.29 (95% CI 1.11 to 1.50) and 1.18 (95% CI 0.98 to 1.42), adjusted for the presence of syndesmophytes at baseline, C-reactive protein at baseline, sex, body mass index (BMI), non-steroidal anti-inflammatory drugs intake score over 2 years, and smoking status at baseline.

Conclusion: Serum leptin and HMW-APN predict protection from spinal radiographic progression in patients with AS. Women generally have higher leptin and HMW-APN serum levels that might explain why they have less structural damage in the spine as compared to male patients with AS.

Trial registration: EudraCT: 2007-007637-39. ClinicalTrials.gov, NCT00715091 . Registered on 14 July 2008.

Keywords: Adipokine; Adiponectin; Ankylosing spondylitis; Axial spondyloarthritis; Leptin; Radiographic progression; Syndesmophytes.

Figures

Fig. 1
Fig. 1
Receiver operating characteristic analysis: association between leptin and high molecular weight adiponectin (HMW-APN) serum levels and radiographic spinal progression after 2 years. Baseline serum levels of leptin and HMW-APN shown as crude values and as values corrected for body mass index and adiponectin (only HMW-APN). mSASSS modified Stoke Ankylosing Spondylitis Spine Score, AUC area under the curve

References

    1. van Tubergen A, Ramiro S, van der Heijde D, Dougados M, Mielants H, Landewe R. Development of new syndesmophytes and bridges in ankylosing spondylitis and their predictors: a longitudinal study. Ann Rheum Dis. 2012;71(4):518–23. doi: 10.1136/annrheumdis-2011-200411.
    1. Landewe R, Dougados M, Mielants H, van der Tempel H, van der Heijde D. Physical function in ankylosing spondylitis is independently determined by both disease activity and radiographic damage of the spine. Ann Rheum Dis. 2009;68(6):863–7. doi: 10.1136/ard.2008.091793.
    1. Machado P, Landewe R, Braun J, Hermann KG, Baker D, van der Heijde D. Both structural damage and inflammation of the spine contribute to impairment of spinal mobility in patients with ankylosing spondylitis. Ann Rheum Dis. 2010;69(8):1465–70. doi: 10.1136/ard.2009.124206.
    1. Baraliakos X, Listing J, von der Recke A, Braun J. The natural course of radiographic progression in ankylosing spondylitis–evidence for major individual variations in a large proportion of patients. J Rheumatol. 2009;36(5):997–1002. doi: 10.3899/jrheum.080871.
    1. Ramiro S, Stolwijk C, van Tubergen A, van der Heijde D, Dougados M, van den Bosch F, et al. Evolution of radiographic damage in ankylosing spondylitis: a 12 year prospective follow-up of the OASIS study. Ann Rheum Dis. 2015;74(1):52–9. doi: 10.1136/annrheumdis-2013-204055.
    1. Ramiro S, van der Heijde D, van Tubergen A, Stolwijk C, Dougados M, van den Bosch F, et al. Higher disease activity leads to more structural damage in the spine in ankylosing spondylitis: 12-year longitudinal data from the OASIS cohort. Ann Rheum Dis. 2014;73(8):1455–61. doi: 10.1136/annrheumdis-2014-205178.
    1. Poddubnyy D, Haibel H, Listing J, Marker-Hermann E, Zeidler H, Braun J, et al. Baseline radiographic damage, elevated acute-phase reactant levels, and cigarette smoking status predict spinal radiographic progression in early axial spondylarthritis. Arthritis Rheum. 2012;64(5):1388–98. doi: 10.1002/art.33465.
    1. Poddubnyy D, Protopopov M, Haibel H, Braun J, Rudwaleit M, Sieper J. High disease activity according to the Ankylosing Spondylitis Disease Activity Score is associated with accelerated radiographic spinal progression in patients with early axial spondyloarthritis: results from the GErman SPondyloarthritis Inception Cohort. Ann Rheum Dis. 2016;75(12):2114–8. doi: 10.1136/annrheumdis-2016-209209.
    1. Baraliakos X, Listing J, Rudwaleit M, Sieper J, Braun J. The relationship between inflammation and new bone formation in patients with ankylosing spondylitis. Arthritis Res Ther. 2008;10(5):R104. doi: 10.1186/ar2496.
    1. van der Heijde D, Machado P, Braun J, Hermann KG, Baraliakos X, Hsu B, et al. MRI inflammation at the vertebral unit only marginally predicts new syndesmophyte formation: a multilevel analysis in patients with ankylosing spondylitis. Ann Rheum Dis. 2012;71(3):369–73. doi: 10.1136/annrheumdis-2011-200208.
    1. Baraliakos X, Heldmann F, Callhoff J, Listing J, Appelboom T, Brandt J, et al. Which spinal lesions are associated with new bone formation in patients with ankylosing spondylitis treated with anti-TNF agents? A long-term observational study using MRI and conventional radiography. Ann Rheum Dis. 2014;73(10):1819–25. doi: 10.1136/annrheumdis-2013-203425.
    1. Machado PM, Baraliakos X, van der Heijde D, Braun J, Landewe R. MRI vertebral corner inflammation followed by fat deposition is the strongest contributor to the development of new bone at the same vertebral corner: a multilevel longitudinal analysis in patients with ankylosing spondylitis. Ann Rheum Dis. 2016;75(8):1486–93. doi: 10.1136/annrheumdis-2015-208011.
    1. Poddubnyy D, Haibel H, Listing J, Marker-Hermann E, Zeidler H, Braun J, et al. Cigarette smoking has a dose-dependent impact on progression of structural damage in the spine in patients with axial spondyloarthritis: results from the GErman SPondyloarthritis Inception Cohort (GESPIC) Ann Rheum Dis. 2013;72(8):1430–2. doi: 10.1136/annrheumdis-2012-203148.
    1. Maksymowych WP, Landewe R, Conner-Spady B, Dougados M, Mielants H, van der Tempel H, et al. Serum matrix metalloproteinase 3 is an independent predictor of structural damage progression in patients with ankylosing spondylitis. Arthritis Rheum. 2007;56(6):1846–53. doi: 10.1002/art.22589.
    1. Poddubnyy D, Conrad K, Haibel H, Syrbe U, Appel H, Braun J, et al. Elevated serum level of the vascular endothelial growth factor predicts radiographic spinal progression in patients with axial spondyloarthritis. Ann Rheum Dis. 2014;73(12):2137–43. doi: 10.1136/annrheumdis-2013-203824.
    1. Turina MC, Sieper J, Yeremenko N, Conrad K, Haibel H, Rudwaleit M, et al. Calprotectin serum level is an independent marker for radiographic spinal progression in axial spondyloarthritis. Ann Rheum Dis. 2014;73(9):1746–8. doi: 10.1136/annrheumdis-2014-205506.
    1. Syrbe U, Callhoff J, Conrad K, Poddubnyy D, Haibel H, Junker S, et al. Serum adipokine levels in patients with ankylosing spondylitis and their relationship to clinical parameters and radiographic spinal progression. Arthritis Rheumatol. 2015;67(3):678–85. doi: 10.1002/art.38968.
    1. Appel H, Ruiz-Heiland G, Listing J, Zwerina J, Herrmann M, Mueller R, et al. Altered skeletal expression of sclerostin and its link to radiographic progression in ankylosing spondylitis. Arthritis Rheum. 2009;60(11):3257–62. doi: 10.1002/art.24888.
    1. Heiland GR, Appel H, Poddubnyy D, Zwerina J, Hueber A, Haibel H, et al. High level of functional dickkopf-1 predicts protection from syndesmophyte formation in patients with ankylosing spondylitis. Ann Rheum Dis. 2012;71(4):572–4. doi: 10.1136/annrheumdis-2011-200216.
    1. Feldtkeller E, Bruckel J, Khan MA. Scientific contributions of ankylosing spondylitis patient advocacy groups. Curr Opin Rheumatol. 2000;12(4):239–47. doi: 10.1097/00002281-200007000-00002.
    1. Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nat Rev Immunol. 2011;11(2):85–97. doi: 10.1038/nri2921.
    1. Neumann E, Junker S, Schett G, Frommer K, Muller-Ladner U. Adipokines in bone disease. Nat Rev Rheumatol. 2016;12(5):296–302. doi: 10.1038/nrrheum.2016.49.
    1. Sieper J, Listing J, Poddubnyy D, Song IH, Hermann KG, Callhoff J, et al. Effect of continuous versus on-demand treatment of ankylosing spondylitis with diclofenac over 2 years on radiographic progression of the spine: results from a randomised multicentre trial (ENRADAS) Ann Rheum Dis. 2016;75(8):1438–43. doi: 10.1136/annrheumdis-2015-207897.
    1. Creemers MC, Franssen MJ, van't Hof MA, Gribnau FW, van de Putte LB, van Riel PL. Assessment of outcome in ankylosing spondylitis: an extended radiographic scoring system. Ann Rheum Dis. 2005;64(1):127–9. doi: 10.1136/ard.2004.020503.
    1. Abella V, Scotece M, Conde J, Lopez V, Lazzaro V, Pino J, et al. Adipokines, Metabolic Syndrome and Rheumatic Diseases. J Immunol Res. 2014;2014:343746. doi: 10.1155/2014/343746.
    1. Neumann E, Frommer KW, Vasile M, Muller-Ladner U. Adipocytokines as driving forces in rheumatoid arthritis and related inflammatory diseases? Arthritis Rheum. 2011;63(5):1159–69. doi: 10.1002/art.30291.
    1. Wang Y, Lam KS, Kraegen EW, Sweeney G, Zhang J, Tso AW, et al. Lipocalin-2 is an inflammatory marker closely associated with obesity, insulin resistance, and hyperglycemia in humans. Clin Chem. 2007;53(1):34–41. doi: 10.1373/clinchem.2006.075614.
    1. Pajvani UB, Hawkins M, Combs TP, Rajala MW, Doebber T, Berger JP, et al. Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J Biol Chem. 2004;279(13):12152–62. doi: 10.1074/jbc.M311113200.
    1. Andreasson AN, Unden AL, Elofsson S, Brismar K. Leptin and adiponectin: distribution and associations with cardiovascular risk factors in men and women of the general population. Am J Hum Biol. 2012;24(5):595–601. doi: 10.1002/ajhb.22279.
    1. Lew J, Sanghavi M, Ayers CR, McGuire DK, Omland T, Atzler D, et al. Sex-based differences in cardiometabolic biomarkers. Circulation. 2017;135(6):544–55. doi: 10.1161/CIRCULATIONAHA.116.023005.
    1. Miranda-Filloy JA, Lopez-Mejias R, Genre F, Carnero-Lopez B, Ochoa R. Diaz de Teran T, et al. Leptin and visfatin serum levels in non-diabetic ankylosing spondylitis patients undergoing TNF-alpha antagonist therapy. Clin Exp Rheumatol. 2013;31(4):538–45.
    1. Toussirot E, Streit G, Nguyen NU, Dumoulin G, Le Huede G, Saas P, et al. Adipose tissue, serum adipokines, and ghrelin in patients with ankylosing spondylitis. Metabolism. 2007;56(10):1383–9. doi: 10.1016/j.metabol.2007.05.009.
    1. Sari I, Demir T, Kozaci LD, Akar S, Kavak T, Birlik M, et al. Body composition, insulin, and leptin levels in patients with ankylosing spondylitis. Clin Rheumatol. 2007;26(9):1427–32. doi: 10.1007/s10067-006-0509-6.
    1. Toussirot E, Grandclement E, Gaugler B, Michel F, Wendling D, Saas P, et al. Serum adipokines and adipose tissue distribution in rheumatoid arthritis and ankylosing spondylitis.A comparative study. Front Immunol. 2013;4:453. doi: 10.3389/fimmu.2013.00453.
    1. Derdemezis CS, Filippatos TD, Voulgari PV, Tselepis AD, Drosos AA, Kiortsis DN. Leptin and adiponectin levels in patients with ankylosing spondylitis. The effect of infliximab treatment. Clin Exp Rheumatol. 2010;28(6):880–3.
    1. Kim KJ, Kim JY, Park SJ, Yoon H, Yoon CH, Kim WU, et al. Serum leptin levels are associated with the presence of syndesmophytes in male patients with ankylosing spondylitis. Clin Rheumatol. 2012;31(8):1231–8. doi: 10.1007/s10067-012-1999-z.
    1. Park MC, Lee SW, Choi ST, Park YB, Lee SK. Serum leptin levels correlate with interleukin-6 levels and disease activity in patients with ankylosing spondylitis. Scand J Rheumatol. 2007;36(2):101–6. doi: 10.1080/03009740600991760.
    1. Mei YJ, Wang P, Chen LJ, Li ZJ. Plasma/serum leptin levels in patients with ankylosing spondylitis: a systematic review and meta-analysis. Arch Med Res. 2016;47(2):111–7. doi: 10.1016/j.arcmed.2016.03.001.
    1. Scotece M, Conde J, Abella V, Lopez V, Pino J, Lago F, et al. Bone metabolism and adipokines: are there perspectives for bone diseases drug discovery? Expert opinion on drug discovery. May. 2014;24:1–13.
    1. Vadacca M, Margiotta DP, Navarini L, Afeltra A. Leptin in immuno-rheumatological diseases. Cell Mol Immunol. 2011;8(3):203–12. doi: 10.1038/cmi.2010.75.
    1. Chen XX, Yang T. Roles of leptin in bone metabolism and bone diseases. J Bone Miner Metab. 2015;33(5):474–85. doi: 10.1007/s00774-014-0569-7.
    1. Thomas T, Gori F, Khosla S, Jensen MD, Burguera B, Riggs BL. Leptin acts on human marrow stromal cells to enhance differentiation to osteoblasts and to inhibit differentiation to adipocytes. Endocrinology. 1999;140(4):1630–8. doi: 10.1210/endo.140.4.6637.
    1. Reseland JE, Syversen U, Bakke I, Qvigstad G, Eide LG, Hjertner O, et al. Leptin is expressed in and secreted from primary cultures of human osteoblasts and promotes bone mineralization. J Bone Miner Res. 2001;16(8):1426–33. doi: 10.1359/jbmr.2001.16.8.1426.
    1. Gordeladze JO, Drevon CA, Syversen U, Reseland JE. Leptin stimulates human osteoblastic cell proliferation, de novo collagen synthesis, and mineralization: Impact on differentiation markers, apoptosis, and osteoclastic signaling. J Cell Biochem. 2002;85(4):825–36. doi: 10.1002/jcb.10156.
    1. Holloway WR, Collier FM, Aitken CJ, Myers DE, Hodge JM, Malakellis M, et al. Leptin inhibits osteoclast generation. J Bone Miner Res. 2002;17(2):200–9. doi: 10.1359/jbmr.2002.17.2.200.
    1. Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell. 2000;100(2):197–207. doi: 10.1016/S0092-8674(00)81558-5.
    1. Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker KL, et al. Leptin regulates bone formation via the sympathetic nervous system. Cell. 2002;111(3):305–17. doi: 10.1016/S0092-8674(02)01049-8.
    1. Elefteriou F, Ahn JD, Takeda S, Starbuck M, Yang X, Liu X, et al. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature. 2005;434(7032):514–20. doi: 10.1038/nature03398.
    1. Hamrick MW, Pennington C, Newton D, Xie D, Isales C. Leptin deficiency produces contrasting phenotypes in bones of the limb and spine. Bone. 2004;34(3):376–83. doi: 10.1016/j.bone.2003.11.020.
    1. Martin A, David V, Malaval L, Lafage-Proust MH, Vico L, Thomas T. Opposite effects of leptin on bone metabolism: a dose-dependent balance related to energy intake and insulin-like growth factor-I pathway. Endocrinology. 2007;148(7):3419–25. doi: 10.1210/en.2006-1541.
    1. Berner HS, Lyngstadaas SP, Spahr A, Monjo M, Thommesen L, Drevon CA, et al. Adiponectin and its receptors are expressed in bone-forming cells. Bone. 2004;35(4):842–9. doi: 10.1016/j.bone.2004.06.008.
    1. Luo XH, Guo LJ, Yuan LQ, Xie H, Zhou HD, Wu XP, et al. Adiponectin stimulates human osteoblasts proliferation and differentiation via the MAPK signaling pathway. Exp Cell Res. 2005;309(1):99–109. doi: 10.1016/j.yexcr.2005.05.021.
    1. Huang CY, Lee CY, Chen MY, Tsai HC, Hsu HC, Tang CH. Adiponectin increases BMP-2 expression in osteoblasts via AdipoR receptor signaling pathway. J Cell Physiol. 2010;224(2):475–83. doi: 10.1002/jcp.22145.
    1. Oshima K, Nampei A, Matsuda M, Iwaki M, Fukuhara A, Hashimoto J, et al. Adiponectin increases bone mass by suppressing osteoclast and activating osteoblast. Biochem Biophys Res Commun. 2005;331(2):520–6. doi: 10.1016/j.bbrc.2005.03.210.
    1. Luo XH, Guo LJ, Xie H, Yuan LQ, Wu XP, Zhou HD, et al. Adiponectin stimulates RANKL and inhibits OPG expression in human osteoblasts through the MAPK signaling pathway. J Bone Miner Res. 2006;21(10):1648–56. doi: 10.1359/jbmr.060707.
    1. Biver E, Salliot C, Combescure C, Gossec L, Hardouin P, Legroux-Gerot I, et al. Influence of adipokines and ghrelin on bone mineral density and fracture risk: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2011;96(9):2703–13. doi: 10.1210/jc.2011-0047.
    1. Sodi R, Hazell MJ, Durham BH, Rees C, Ranganath LR, Fraser WD. The circulating concentration and ratio of total and high molecular weight adiponectin in post-menopausal women with and without osteoporosis and its association with body mass index and biochemical markers of bone metabolism. Clin Biochem. 2009;42(13-14):1375–80. doi: 10.1016/j.clinbiochem.2009.06.003.
    1. Hara K, Horikoshi M, Yamauchi T, Yago H, Miyazaki O, Ebinuma H, et al. Measurement of the high-molecular weight form of adiponectin in plasma is useful for the prediction of insulin resistance and metabolic syndrome. Diabetes Care. 2006;29(6):1357–62. doi: 10.2337/dc05-1801.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren