Document Type : Original Article

Authors

1 Drug Applied Research Center, Connective Tissue Diseases Research Center, Department of Rheumatology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

2 Drug Applied Research Center, Connective Tissue Diseases Research Center, Department of Biochemistry, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

3 Drug Applied Research Center, Connective Tissue Diseases Research Center, Department of Nephrology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

Abstract

Rheumatoid arthritis (RA) is one of most important collagen vascular diseases. It has an unknown origin. The aim of this study was to evaluate circulating levels of osteoprotegerin (OPG), total soluble receptor activator of nuclear factor-Kappa B ligand (total sRANKL), and RANKL/OPG ratio in patients with RA. Forty-five females with RA, who fulfilled the American college of rheumatology (ACR) criteria for RA were included in this cross-sectional study. The overall disease activity was evaluated by the disease activity score based on 28 joint counts (DAS-28). The OPG and sRANKL were measured by the enzyme-linked immunosorbent assays (ELISA). The levels of C-reactive protein (CRP) were measured by ELISA.We used Pearson’s correlation for our comparisons. There was no statistically significant difference between the levels of CRP, OPG, sRANKL and RANKL/OPG ratio in terms of DAS-28 grades in our patients. No significant correlation was found between the serum levels of OPG and DAS-28 (P= 0.525), duration of the disease (P= 0.884), Z-score of the femur (P= 0.546) and Z-score of the spine (P= 0.492), T-score of the femur (P= 0.137) and T-score of the spine (P= 0.821) in the patient group. No significant correlations were found between sRANKL levels with DAS-28 (0.919), Z-score of the femur (P= 0.971), Z-score of the spine (P= 0.832) and T-score of the femur (P = 0170) in the studied groups. Our study showed that there was no significant correlation between CRP, OPG, sRANKL and RANKL/OPG ratio in DAS-28 grading of our patients. For this reason they will not be used for evaluating disease activity. However, there was a significant difference between case and control groups except for sRANKL (pg/mL).

Keywords

Carlsen H, Moskaug JO, Fromm SH, Blomhoff R. In vivo imaging of NFkappa B activity. J Immunol. 2002; 168(3):1441-6.
Gal I, Bajnok E, Szanto S, Sarraj B, Glant TT, Mikecz K. Visualization and in situ analysis of leukocyte trafficking into the ankle joint in a systemic murine model of rheumatoid arthritis. Arthritis Rheum. 2005; 52(10): 3269-78. doi: 10.1002/art.21532.
Amaya-Amaya J, Sarmiento-Monroy JC, Mantilla RD, Pineda-Tamayo R, Rojas-Villarraga A, Anaya JM. Novel risk factors for cardiovascular disease in rheumatoid arthritis. Immunol Res. 2013; 56(2-3): 267-86. doi: 10.1007/s12026-013-8398-7.
Fiehn C. [Rheumatoid arthritis - cardiovascular risk is high, but manageable]. Dtsch Med Wochenschr. 2013; 138(14): 744. doi: 10.1055/s-0032-1333056.
Ozbalkan Z, Efe C, Cesur M, Ertek S, Nasiroglu N, Berneis K, et al. An update on the relationships between rheumatoid arthritis and atherosclerosis. Atherosclerosis. 2010; 212(2): 377-82. doi: 10.1016/j. atherosclerosis. 2010.03.035.
Bijl M. Endothelial activation, endothelial dysfunction and premature atherosclerosis in systemic autoimmune diseases. Neth J Med. 2003; 61(9): 273-7.
Paccou J, Brazier M, Mentaverri R, Kamel S, Fardellone P, Massy ZA. Vascular calcification in rheumatoid arthritis: prevalence, pathophysiological aspects and potential targets. Atherosclerosis. 2012; 224(2): 283-90. doi: 10.1016/j.atherosclerosis.2012.04.008.
Rho YH, Chung CP, Oeser A, Solus J, Asanuma Y, Sokka T, et al. Inflammatory mediators and premature coronary atherosclerosis in rheumatoid arthritis. Arthritis Rheum. 2009; 61(11): 1580-5. doi: 10.1002/art. 25009.
Rauner M, Sipos W, Pietschmann P. Osteoimmunology. Int Arch Allergy Immunol. 2007; 143(1): 31-48. doi: 10.1159/000098223.
Tanaka Y. [Rheumatoid arthritis and osteoporosis: trends in theirtreatments]. Nihon Rinsho. 2006; 64(12): 2359-66.
Strand V, Kavanaugh AF. The role of interleukin-1 in bone resorption in rheumatoid arthritis. Rheumatology (Oxford). 2004; 43 Suppl 3: 10-6. doi: 10.1093/ rheumatology/keh202.
Kearns AE, Khosla S, Kostenuik PJ. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev. 2008; 29(2): 155-92. doi: 10.1210/er. 2007-0014.
Jorgensen C. Mesenchymal stem cells in arthritis: role of bone marrow microenvironment. Arthritis Res Ther. 2010; 12(4): 135. doi: 10.1186/ar3105.
Walsh NC, Gravallese EM. Bone remodeling in rheumatic disease: a question of balance. Immunol Rev. 2010; 233(1): 301-12. doi: 10.1111/j.0105-2896.2009.00857. x.
Fili S, Karalaki M, Schaller B. Therapeutic implications of osteoprotegerin. Cancer Cell Int. 2009; 9: 26. doi: 10.1186/1475-2867-9-26.
Leibbrandt A, Penninger JM. RANKL/RANK as key factors for osteoclast development and bone loss in arthropathies. Adv Exp Med Biol. 2009; 649: 100-13.
Wada T, Nakashima T, Hiroshi N, Penninger JM. RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med. 2006; 12(1): 17-25. doi: 10.1016/j. molmed.2005.11.007.
Fu Q, Jilka RL, Manolagas SC, O’Brien CA. Parathyroid hormone stimulates receptor activator of NFkappa B ligand and inhibits osteoprotegerin expression via protein kinase A activation of cAMP-response element-binding protein. J Biol Chem. 2002; 277(50): 48868-75. doi: 10.1074/jbc.M208494200.
Spelling P, Bonfa E, Caparbo VF, Pereira RM. Osteoprotegerin/ RANKL system imbalance in active polyarticular-onset juvenile idiopathic arthritis: a bone damage biomarker?. Scand JRheumatol. 2008; 37(6): 439-44. doi: 10.1080/03009740802116224.
Wasilewska A, Rybi-Szuminska AA, Zoch-Zwierz W. Serum osteoprotegrin (OPG) and receptor activator of nuclear factor kappaB (RANKL) in healthy children and adolescents. J Pediatr Endocrinol Metab. 2009; 22(12): 1099-104.
Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988; 31(3): 315-24.
Kiechl S, Werner P, Knoflach M, Furtner M, Willeit J, Schett G. The osteoprotegerin/ RANK/ RANKL system: a bone key to vascular disease. Expert Rev Cardiovasc Ther. 2006; 4(6): 801-11. doi: 10.1586/14779072.4. 6.801.
Kanis JA, Melton LJ, Christiansen C, Johnston CC, Khaltaev N. The diagnosis of osteoporosis. J Bone Miner Res. 1994; 9(8): 1137-41. doi: 10.1002/jbmr.5650090802.
Klejna K, Naumnik B, Gasowska K, Mysliwiec M. OPG/ RANK/ RANKL signaling system and its significance in nephrology. Folia Histochem Cytobiol. 2009; 47(2): 199-206. doi: 10.2478/v10042-009-0035-x.
Gaudio A, Lasco A, Morabito N, Atteritano M, Vergara C, Catalano A, et al. Hepatic osteodystrophy: does the osteoprotegerin/receptor activator of nuclear factor-kB ligand system play a role?. J Endocrinol Invest. 2005; 28(8): 677-82.
Hofbauer LC, Heufelder AE. Role of receptor activator of nuclear factor-kappaB ligand and osteoprotegerin in bone cell biology. J Mol Med (Berl). 2001; 79(5-6): 243-53.
Tat SK, Padrines M, Theoleyre S, Couillaud-Battaglia S, Heymann D, Redini F, et al. OPG/ membranous–RANKL complex is internalized via the clathrin pathway before a lysosomal and a Kolahi et al.proteasomal degradation. Bone. 2006; 39(4): 706-15. doi: 10.1016/j.bone.2006.03.016.
Nakamura H, Kumei Y, Morita S, Shimokawa H, Ohya K, Shinomiya K. Suppression of osteoblastic phenotypes and modulation of pro- and anti-apoptotic features in normal human osteoblastic cells under a vector-averaged gravity condition. J Med Dent Sci. 2003; 50(2): 167-76.
Kobayashi-Sakamoto M, Hirose K, Nishikata M, Isogai E, Chiba I. Osteoprotegerin protects endothelial cells against apoptotic cell death induced by Porphyromonas gingivalis cysteine proteinases. FEMS Microbiol Lett. 2006; 264(2): 238-45. doi: 10.1111/j.1574-6968.2006.00458.x.
Wallin R, Wajih N, Greenwood GT, Sane DC. Arterial calcification: a review of mechanisms, animal models, and the prospects for therapy. Med Res Rev. 2001; 21(4): 274-301.
Min H, Morony S, Sarosi I, Dunstan CR, Capparelli C, Scully S, et al. Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis. J Exp Med. 2000; 192(4): 463-74.
Anand DV, Lim E, Darko D, Bassett P, Hopkins D, Lipkin D, et al. Determinants of progression of coronary artery calcification in type 2 diabetes role of glycemic control and inflammatory/ vascular calcification markers. J Am Coll Cardiol. 2007; 50(23): 2218-25. doi: 10.1016/j.jacc. 2007.08.032.
Breland UM, Hollan I, Saatvedt K, Almdahl SM, Damas JK, Yndestad A, et al. Inflammatory markers in patients with coronary artery disease with and without inflammatory rheumatic disease. Rheumatology (Oxford). 2010; 49(6): 1118-27. doi: 10.1093/ rheumatology/keq005.
Ziolkowska M, Kurowska M, Radzikowska A, Luszczykiewicz G, Wiland P, Dziewczopolski W, et al. High levels of osteoprotegerin and soluble receptor activator of nuclear factor kappa B ligand in serum of rheumatoid arthritis patients and their normalization after anti-tumor necrosis factor alpha treatment. Arthritis Rheum. 2002; 46(7): 1744-53. doi: 10.1002/art.10388.
Gonzalez-Alvaro I, Ortiz AM, Tomero EG, Balsa A, Orte J, Laffon A, et al. Baseline serum RANKL levels may serve to predict remission in rheumatoid arthritis patients treated with TNFantagonists. Ann Rheum Dis. 2007; 66(12): 1675-8. doi: 10.1136/ard.2007.071910.
Xu S, Wang Y, Lu J, Xu J. Osteoprotegerin and RANKL in the pathogenesis of rheumatoid arthritis-induced osteoporosis. Rheumatol Int. 2012; 32(11): 3397-403. doi: 10.1007/s00296-011-2175-5.
Ueland T, Bollerslev J, Wilson SG, Dick IM, Islam FM, Mullin BH, et al. No associations between OPG gene polymorphisms or serum levels and measures of osteoporosis in elderly Australian women. Bone. 2007; 40(1): 175-81. doi: 10.1016/j.bone.2006.06.022.
Bezerra MC, Calomeni GD, Caparbo VF, Gebrim ES, Rocha MS, Pereira RM. Low bone density and low serum levels of soluble RANK ligand are associated with severe arterial calcification in patients with Takayasu arteritis. Rheumatology (Oxford). 2005; 44(12): 1503-6. doi: 10.1093/rheumatology/kei045.
Zupan J, Jeras M, Marc J. Osteoimmunology and the influence of pro-inflammatory cytokines on osteoclasts. Biochem Med (Zagreb). 2013; 23(1): 43-63.