Circulating Levels of Soluble Receptor Activator of NF-κB Ligand and Matrix Metalloproteinase 3 (and Their Antagonists) in Asian Indian Patients with Ankylosing Spondylitis
Background. Bone loss in ankylosing spondylitis may be related to inflammation. Data from previous studies on circulating levels of sRANKL, OPG, MMP3, and TIMP is inconsistent; thus this study is planned to look at this aspect in Asian Indian patients. Methods. Cross-sectional study included patients with ankylosing spondylitis and age- and gender-similar controls. Serum levels of sRANKL, OPG, MMP-3, and TIMP-1 were measured by ELISA. Results. Included 85 patients (M?:?F = 82?:?3) having mean age (±SD) years and disease duration years. BASDAI, BASFI, BASMI, and ESR were , , and respectively. Patients had higher mean (±SD) OPG level ( , ?pg/mL, ). However, there was no difference in sRANKL ( , , ). Serum MMP-3 ( , ?ng/mL, ) and TIMP-1 ( , ?ng/mL, ) levels were higher in patients; however, there was no difference in MMP-3/TIMP-1 ratio. Conclusion. Circulating levels of OPG were higher; however, there was no difference in sRANKL in Asian Indian ankylosing spondylitis patients. Although both MMP-3 and TIMP-1 were raised, their ratio was not different from that of controls. 1. Introduction Patients with ankylosing spondylitis have been shown to have low bone mineral density at spine and propensity for vertebral fractures. The loss of bone mineral density has been shown to be more marked in late than early disease [1]. The bone loss may be related to inflammation, as in other chronic inflammatory diseases [2, 3]. Indeed, ankylosing spondylitis is characterized by chronic inflammation, as evidenced by elevated proinflammatory cytokines like tumour necrosis factor-α (TNFα) and interleukin-6 [4]. These may lead to bone loss by increased expression of receptor activator of NF-κB ligand (RANKL) on osteoblasts and stromal cells and its soluble form (sRANKL). RANKL and cytokines lead to osteoclast and other inflammatory cell activation and release of bone and cartilage degrading enzymes like cathepsin K and matrix metalloproteinases (MMPs) [5, 6]. Their natural antagonists, that is, osteoprotegerin (for RANKL) and tissue inhibitor of metalloproteinase or TIMP (for MMP) oppose their actions. Among the MMPs, there is promising data on the association of disease activity with MMP-3 [7]. There is inconsistent data on circulating levels of these molecules in ankylosing spondylitis, especially in Asian Indians. Thus this study was planned to look at levels of these molecules in this population. 2. Methods 2.1. Study Design This cross-sectional study was carried out in a North Indian university hospital between April 2010 and February 2011. Institutional ethical clearance
References
[1]
Y. S. L. Lee, T. Schlotzhauer, S. M. Ott et al., “Skeletal status of men with early and late ankylosing spondylitis,” American Journal of Medicine, vol. 103, no. 3, pp. 233–241, 1997.
[2]
A. El Maghraoui, “Osteoporosis and ankylosing spondylitis,” Joint Bone Spine, vol. 71, no. 4, pp. 291–295, 2004.
[3]
P. Geusens, D. Vosse, and S. van der Linden, “Osteoporosis and vertebral fractures in ankylosing spondylitis,” Current Opinion in Rheumatology, vol. 19, no. 4, pp. 335–339, 2007.
[4]
C. Roux, “Osteoporosis in inflammatory joint diseases,” Osteoporosis International, vol. 22, no. 2, pp. 421–433, 2011.
[5]
K. Redlich and J. S. Smolen, “Inflammatory bone loss: pathogenesis and therapeutic intervention,” Nature Reviews Drug Discovery, vol. 11, no. 3, pp. 234–250, 2012.
[6]
D. M. Findlay and G. J. Atkins, “Relationship between serum RANKL and RANKL in bone,” Osteoporosis International, vol. 22, no. 10, pp. 2597–2602, 2011.
[7]
C.-H. Chen, K.-C. Lin, D. T. Y. Yu et al., “Serum matrix metalloproteinases and tissue inhibitors of metalloproteinases in ankylosing spondylitis: MMP-3 is a reproducibly sensitive and specific biomarker of disease activity,” Rheumatology, vol. 45, no. 4, pp. 414–420, 2006.
[8]
S. van der Linden, H. A. Valkenburg, and A. Cats, “Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria,” Arthritis and Rheumatism, vol. 27, no. 4, pp. 361–368, 1984.
[9]
S. Garrett, T. Jenkinson, L. G. Kennedy, H. Whitelock, P. Gaisford, and A. Calin, “A new approach to defining disease status in ankylosing spondylitis: the bath ankylosing spondylitis disease activity index,” Journal of Rheumatology, vol. 21, no. 12, pp. 2286–2291, 1994.
[10]
A. Calin, S. Garrett, H. Whitelock, J. O'Hea, P. Mallorie, and T. Jenkinson, “A new approach to defining functional ability in ankylosing spondylitis: the development of the bath ankylosing spondylitis functional index,” Journal of Rheumatology, vol. 21, no. 12, pp. 2281–2285, 1994.
[11]
T. R. Jenkinson, P. A. Mallorie, H. C. Whitelock, L. G. Kennedy, S. L. Garrett, and A. Calin, “Defining spinal mobility in ankylosing spondylitis (AS). The Bath AS metrology index,” Journal of Rheumatology, vol. 21, no. 9, pp. 1694–1698, 1994.
[12]
J. Grisar, P. M. Bernecker, M. Aringer et al., “Ankylosing spondylitis, psoriatic arthritis, and reactive arthritis show increased bone resorption, but differ with regard to bone formation,” Journal of Rheumatology, vol. 29, no. 7, pp. 1430–1436, 2002.
[13]
R. P. Golmia, B. D. B. Sousa, M. A. Scheinberg, J. Gratacós, and R. Sanmarti, “Increased osteoprotegerin and decreased pyridinoline levels in patients with ankylosing spondylitis: comment on the article by Gratacós et al,” Arthritis and Rheumatism, vol. 46, no. 12, pp. 3390–3391, 2002.
[14]
C. Chen, H. Chen, H. Liao, C. Liu, C. Tsai, and C. Chou, “Soluble receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin in ankylosing spondylitis: OPG is associated with poor physical mobility and reflects systemic inflammation,” Clinical Rheumatology, vol. 29, no. 10, pp. 1155–1161, 2010.
[15]
H.-R. Kim, H.-Y. Kim, and S. Lee, “Elevated serum levels of soluble receptor activator of nuclear factors-κB ligand (sRANKL) and reduced bone mineral density in patients with ankylosing spondylitis (AS),” Rheumatology, vol. 45, no. 10, pp. 1197–1200, 2006.
[16]
H. Franck, T. Meurer, and L. C. Hofbauer, “Evaluation of bone mineral density, hormones, biochemical markers of bone metabolism, and osteoprotegerin serum levels in patients with ankylosing spondylitis,” Journal of Rheumatology, vol. 31, no. 11, pp. 2236–2241, 2004.
[17]
D. R. Haynes, E. Barg, T. N. Crotti et al., “Osteoprotegerin expression in synovial tissue from patients with rheumatoid arthritis, spondyloarthropathies and osteoarthritis and normal controls,” Rheumatology, vol. 42, no. 1, pp. 123–134, 2003.
[18]
B. Vandooren, T. Cantaert, T. Noordenbos, P. P. Tak, and D. Baeten, “The abundant synovial expression of the RANK/RANKL/osteoprotegerin system in peripheral spondylarthritis is partially disconnected from inflammation,” Arthritis and Rheumatism, vol. 58, no. 3, pp. 718–729, 2008.
[19]
W. P. Maksymowych, R. Landewé, B. Conner-Spady et al., “Serum matrix metalloproteinase 3 is an independent predictor of structural damage progression in patients with ankylosing spondylitis,” Arthritis and Rheumatism, vol. 56, no. 6, pp. 1846–1853, 2007.
[20]
M. Neidhart, X. Baraliakos, C. Seemayer et al., “Expression of cathepsin K andmatrixmetalloproteinase 1 indicate persistent osteodestructive activity in longstanding ankylosing spondylitis,” Annals of the Rheumatic Diseases, vol. 68, no. 8, pp. 1334–1339, 2009.
[21]
M. Rauner, D. Stupphann, M. Haas et al., “The HLA-B27 transgenic rat, a model of spondyloarthritis, has decreased bone mineral density and increased RANKL to osteoprotegerin mRNA ratio,” Journal of Rheumatology, vol. 36, no. 1, pp. 120–126, 2009.
[22]
J. Woo, H. Lee, I. L.-H. Sung, and T. Kim, “Changes of clinical response and bone biochemical markers in patients with ankylosing spondylitis taking etanercept,” Journal of Rheumatology, vol. 34, no. 8, pp. 1753–1759, 2007.
[23]
M. Gengenbacher, H.-J. Sebald, P. M. Villiger, W. Hofstetter, and M. Seitz, “Infliximab inhibits bone resorption by circulating osteoclast precursor cells in patients with rheumatoid arthritis and ankylosing spondylitis,” Annals of the Rheumatic Diseases, vol. 67, no. 5, pp. 620–624, 2008.
[24]
B. Vandooren, E. Kruithof, D. T. Y. Yu et al., “Involvement of matrix metalloproteinases and their inhibitors in peripheral synovitis and down-regulation by tumor necrosis factor α blockade in spondylarthropathy,” Arthritis and Rheumatism, vol. 50, no. 9, pp. 2942–2953, 2004.
[25]
C. Am?linei, I. D. C?runtu, and R. A. B?lan, “Biology of metalloproteinases,” Romanian Journal of Morphology and Embryology, vol. 48, pp. 323–334, 2007.
[26]
K. Kusano, C. Miyaura, M. Inada et al., “Regulation of matrix metalloproteinases (MMP-2,-3,-9, and -13) by interleukin-1 and interleukin-6 in mouse calvaria: association of MMP induction with bone resorption,” Endocrinology, vol. 139, no. 3, pp. 1338–1345, 1998.
[27]
D. L. Mattey, J. C. Packham, N. B. Nixon et al., “Association of cytokine and matrix metalloproteinase profiles with disease activity and function in ankylosing spondylitis,” Arthritis Research & Therapy, vol. 14, article R127, 2012.
[28]
E. Soliman, W. Labib, G. El-tantawi, A. Hamimy, A. Alhadidy, and A. Aldawoudy, “Role of matrix metalloproteinase-3 (MMP-3) and magnetic resonance imaging of sacroiliitis in assessing disease activity in ankylosing spondylitis,” Rheumatology International, vol. 32, pp. 1711–1720, 2012.
[29]
D. Wendling, J. Cedoz, and E. Racadot, “Serum levels of MMP-3 and cathepsin K in patients with ankylosing spondylitis: effect of TNFα antagonist therapy,” Joint Bone Spine, vol. 75, no. 5, pp. 559–562, 2008.