Abstract
Various studies have investigated the serum sclerostin and bone morphogenetic protein-2 (BMP-2) levels in patients with ankylosing spondylitis (AS), but the results were inconsistent. The aim of this meta-analysis was to synthetically assess the associations of serum levels of sclerostin and BMP-2 with AS. Multiple electronic databases were searched to locate relevant articles published before November 2018. Pooled standard mean difference (SMD) with 95% confidence interval (CI) was calculated by the random-effect model. Totally, 21 studies were included. Meta-analysis results showed no significant difference between AS group and control group in serum sclerostin levels (SMD = 0.098, 95% CI − 0.395 to 0.591, p = 0.697). Nevertheless, serum BMP-2 levels in AS patients were higher than that in controls (SMD = 1.184, 95% CI 0.209 to 2.159, p = 0.017). Subgroup analysis demonstrated that European and South American AS patients had lower serum levels of sclerostin than controls. AS patients with age ≥ 40 years, erythrocyte sedimentation rate (ESR) ≤ 20 mm/h and Bath Ankylosing Spondylitis Functional Index (BASFI) < 4 had statistically significant lower serum sclerostin concentrations compared to controls. Chinese and Korean AS patients as well as patients with lower CRP had higher serum BMP-2 levels than controls, and country may be a source of heterogeneity across the studies. No publication bias existed and sensitivity analysis confirmed the stability of results. Serum BMP-2, but not sclerostin levels may be closely related to the development of AS.
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References
Braun J, Sieper J (2007) Ankylosing spondylitis. Lancet 369(9570):1379–1390. https://doi.org/10.1016/s0140-6736(07)60635-7
Machado P, Landewe R, Braun J, Hermann KG, Baker D, van der Heijde D (2010) Both structural damage and inflammation of the spine contribute to impairment of spinal mobility in patients with ankylosing spondylitis. Ann Rheumat Dis 69(8):1465–1470. https://doi.org/10.1136/ard.2009.124206
Perrotta FM, Ceccarelli F (2018) Serum sclerostin as a possible biomarker in ankylosing spondylitis: a case-control study. J Immunol Res. https://doi.org/10.1155/2018/9101964
Liao HT, Lin YF, Tsai CY, Chou TC (2018) Bone morphogenetic proteins and Dickkopf-1 in ankylosing spondylitis. Scandin J Rheumatol 47(1):56–61. https://doi.org/10.1080/03009742.2017.1287305
Moester MJ, Papapoulos SE, Lowik CW, van Bezooijen RL (2010) Sclerostin: current knowledge and future perspectives. Calcif Tissue Int 87(2):99–107. https://doi.org/10.1007/s00223-010-9372-1
Baron R, Rawadi G (2007) Targeting the Wnt/beta-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology 148(6):2635–2643. https://doi.org/10.1210/en.2007-0270
Zhou Y, Wang T, Hamilton JL, Chen D (2017) Wnt/beta-catenin signaling in osteoarthritis and in other forms of arthritis. Curr Rheumatol Rep 19(9):53. https://doi.org/10.1007/s11926-017-0679-z
Lories RJ, Luyten FP (2007) Bone morphogenetic proteins in destructive and remodeling arthritis. Arthrit Res Therapy 9(2):207. https://doi.org/10.1186/ar2135
Hsu WK, Wang JC (2008) The use of bone morphogenetic protein in spine fusion. Spine J 8(3):419–425. https://doi.org/10.1016/j.spinee.2008.01.008
Liu T, Gao Y, Sakamoto K, Minamizato T, Furukawa K, Tsukazaki T, Shibata Y, Bessho K, Komori T, Yamaguchi A (2007) BMP-2 promotes differentiation of osteoblasts and chondroblasts in Runx2-deficient cell lines. J Cell Physiol 211(3):728–735. https://doi.org/10.1002/jcp.20988
Nakashima K, de Crombrugghe B (2003) Transcriptional mechanisms in osteoblast differentiation and bone formation. Trends Genet TIG 19(8):458–466. https://doi.org/10.1016/s0168-9525(03)00176-8
Rawadi G, Vayssiere B, Dunn F, Baron R, Roman-Roman S (2003) BMP-2 controls alkaline phosphatase expression and osteoblast mineralization by a Wnt autocrine loop. J Bone Mineral Res 18(10):1842–1853. https://doi.org/10.1359/jbmr.2003.18.10.1842
Fukuda T, Kokabu S, Ohte S, Sasanuma H, Kanomata K, Yoneyama K, Kato H, Akita M, Oda H, Katagiri T (2010) Canonical Wnts and BMPs cooperatively induce osteoblastic differentiation through a GSK3beta-dependent and beta-catenin-independent mechanism. Differentiation 80(1):46–52. https://doi.org/10.1016/j.diff.2010.05.002
Zhang R, Oyajobi BO, Harris SE, Chen D, Tsao C, Deng HW, Zhao M (2013) Wnt/beta-catenin signaling activates bone morphogenetic protein 2 expression in osteoblasts. Bone 52(1):145–156. https://doi.org/10.1016/j.bone.2012.09.029
Genre F, Rueda-Gotor J, Remuzgo-Martinez S, Corrales A, Ubilla B, Mijares V, Fernandez-Diaz C, Portilla V, Blanco R, Hernandez JL, Llorca J, Lopez-Mejias R, Gonzalez-Gay MA (2018) Implication of osteoprotegerin and sclerostin in axial spondyloarthritis cardiovascular disease: study of 163 Spanish patients. Clin Exp Rheumatol 36(2):302–309. https://doi.org/10.3899/jrheum.170833
Sakellariou GT, Iliopoulos A, Konsta M, Kenanidis E, Potoupnis M, Tsiridis E, Gavana E, Sayegh FE (2017) Serum levels of Dkk-1, sclerostin and VEGF in patients with ankylosing spondylitis and their association with smoking, and clinical, inflammatory and radiographic parameters. Joint Bone Spine 84(3):309–315. https://doi.org/10.1016/j.jbspin.2016.05.008
Xie Z, Wang P, Li Y, Deng W, Zhang X, Su H, Li D, Wu Y, Shen H (2016) Imbalance between bone morphogenetic protein 2 and noggin induces abnormal osteogenic differentiation of mesenchymal stem cells in ankylosing spondylitis. Arthrit Rheumatol 68(2):430–440. https://doi.org/10.1002/art.39433
Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in epidemiology (MOOSE) group. JAMA 283(15):2008–2012
Wan X, Wang W, Liu J, Tong T (2014) Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 14:135. https://doi.org/10.1186/1471-2288-14-135
Luo D, Wan X, Liu J, Tong T (2018) Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res 27(6):1785–1805. https://doi.org/10.1177/0962280216669183
Sun W, Tian L, Jiang L, Zhang S, Zhou M, Zhu J, Xue J (2018) Sclerostin rather than Dickkopf-1 is associated with mSASSS but not with disease activity score in patients with ankylosing spondylitis. Clin Rheumatol. https://doi.org/10.1007/s10067-018-4356-z
Luchetti MM, Ciccia F, Avellini C, Benfaremo D, Guggino G, Farinelli A, Ciferri M, Rossini M, Svegliati S, Spadoni T, Bolognini L, Fava G, Mosca P, Gesuita R, Skrami E, Triolo G, Gabrielli A (2018) Sclerostin and anti sclerostin antibody serum levels predict the presence of axial spondyloarthritis in patients with inflammatory bowel disease. J Immunol Res 45(5):630–637. https://doi.org/10.1155/2018/910196410.3899/jrheum.170833
Niu CC, Lin SS, Yuan LJ, Chen LH, Yang CY, Chung AN, Lu ML, Tsai TT, Lai PL, Chen WJ (2017) Correlation of blood bone turnover biomarkers and Wnt signaling antagonists with AS, DISH, OPLL, and OYL. BMC musculoskeletal disorders 18(1):61. https://doi.org/10.1186/s12891-017-1425-4
Tian L, Zhou M, Zhang S, Xue J (2017) Correlation analysis of serum osteotin level and bone imaging changes in patients with ankylosing spondylitis. Zhejiang clinical medicine 19(8):1394–1396
Lu Z, Guan Z (2017) Serum levels of Dickkopf-1, sclerostin and vascular endothelial growth factor A and their correlation with ankylosing spondylitis progression. Chin J Tissue Eng Res 21(32):5085–5090
Rossini M, Viapiana O, Idolazzi L, Ghellere F, Fracassi E, Troplini S, Povino MR, Kunnathully V, Adami S, Gatti D (2016) Higher level of Dickkopf-1 is associated with low bone mineral density and higher prevalence of vertebral fractures in patients with ankylosing spondylitis. Calcif Tissue Int 98(5):438–445. https://doi.org/10.1007/s00223-015-0093-3
Xie J, Yu X (2015) [Correlation between sclerostin level and radiographic changes in patients with ankylosing spondylitis]. Zhonghua yi xue za zhi 95(17):1300–1304
Klingberg E, Nurkkala M, Carlsten H, Forsblad-d’Elia H (2014) Biomarkers of bone metabolism in ankylosing spondylitis in relation to osteoproliferation and osteoporosis. J Rheumatol 41(7):1349–1356. https://doi.org/10.3899/jrheum.131199
Tuylu T, Sari I, Solmaz D, Kozaci DL, Akar S, Gunay N, Onen F, Akkoc N (2014) Fetuin-A is related to syndesmophytes in patients with ankylosing spondylitis: a case control study. Clinics (Sao Paulo Brazil) 69(10):688–693. https://doi.org/10.6061/clinics/2014(10)07
Ustun N, Tok F, Kalyoncu U, Motor S, Yuksel R, Yagiz AE, Guler H, Turhanoglu AD (2014) Sclerostin and Dkk-1 in patients with ankylosing spondylitis. Acta Reumatol port 39(2):146–151
Korkosz M, Gasowski J, Leszczynski P, Pawlak-Bus K, Jeka S, Kucharska E, Grodzicki T (2013) High disease activity in ankylosing spondylitis is associated with increased serum sclerostin level and decreased wingless protein-3a signaling but is not linked with greater structural damage. BMC Musculoskelet Disord 14:99. https://doi.org/10.1186/1471-2474-14-99
Taylan A, Sari I, Akinci B, Bilge S, Kozaci D, Akar S, Colak A, Yalcin H, Gunay N, Akkoc N (2012) Biomarkers and cytokines of bone turnover: extensive evaluation in a cohort of patients with ankylosing spondylitis. BMC Musculoskelet Disord 13:191. https://doi.org/10.1186/1471-2474-13-191
Saad CG, Ribeiro AC, Moraes JC, Takayama L, Goncalves CR, Rodrigues MB, de Oliveira RM, Silva CA, Bonfa E, Pereira RM (2012) Low sclerostin levels: a predictive marker of persistent inflammation in ankylosing spondylitis during anti-tumor necrosis factor therapy? Arthritis Res Therapy 14(5):R216. https://doi.org/10.1186/ar4055
Appel H, Ruiz-Heiland G, Listing J, Zwerina J, Herrmann M, Mueller R, Haibel H, Baraliakos X, Hempfing A, Rudwaleit M, Sieper J, Schett G (2009) Altered skeletal expression of sclerostin and its link to radiographic progression in ankylosing spondylitis. Arthritis Rheum 60(11):3257–3262. https://doi.org/10.1002/art.24888
Chen HA, Chen CH, Lin YJ, Chen PC, Chen WS, Lu CL, Chou CT (2010) Association of bone morphogenetic proteins with spinal fusion in ankylosing spondylitis. J Rheumatol 37(10):2126–2132. https://doi.org/10.3899/jrheum.100200
Park MC, Park YB, Lee SK (2008) Relationship of bone morphogenetic proteins to disease activity and radiographic damage in patients with ankylosing spondylitis. Scand J Rheumatol 37(3):200–204. https://doi.org/10.1080/03009740701774941
Chen Z, Wang S, Zhu G (2015) The relationship between serum ossification and mSASSS score in ankylosing spondylitis patients. World Latest Med Inf 15(83):1–3
Ke HZ, Richards WG, Li X, Ominsky MS (2012) Sclerostin and Dickkopf-1 as therapeutic targets in bone diseases. Endocr Rev 33(5):747–783. https://doi.org/10.1210/er.2011-1060
Stolina M, Dwyer D, Niu QT, Villasenor KS, Kurimoto P, Grisanti M, Han CY, Liu M, Li X, Ominsky MS, Ke HZ, Kostenuik PJ (2014) Temporal changes in systemic and local expression of bone turnover markers during six months of sclerostin antibody administration to ovariectomized rats. Bone 67:305–313. https://doi.org/10.1016/j.bone.2014.07.031
Wildemann B, Burkhardt N, Luebberstedt M, Vordemvenne T, Schmidmaier G (2007) Proliferating and differentiating effects of three different growth factors on pluripotent mesenchymal cells and osteoblast like cells. J Orthop Surg Res 2:27. https://doi.org/10.1186/1749-799x-2-27
Katagiri T, Yamaguchi A, Komaki M, Abe E, Takahashi N, Ikeda T, Rosen V, Wozney JM, Fujisawa-Sehara A, Suda T (1994) Bone morphogenetic protein-2 converts the differentiation pathway of C2C12 myoblasts into the osteoblast lineage. J Cell Biol 127(6 Pt 1):1755–1766
Cortes A, Maksymowych WP, Wordsworth BP, Inman RD, Danoy P, Rahman P, Stone MA, Corr M, Gensler LS, Gladman D, Morgan A, Marzo-Ortega H, Ward MM, Learch TJ, Reveille JD, Brown MA, Weisman MH (2015) Association study of genes related to bone formation and resorption and the extent of radiographic change in ankylosing spondylitis. Ann Rheum Dis 74(7):1387–1393. https://doi.org/10.1136/annrheumdis-2013-204835
Shi J, Ying H, Du J, Shen B (2017) Serum sclerostin levels in patients with ankylosing spondylitis and rheumatoid arthritis: a systematic review and meta-analysis. Biomed Res Int 2017:9295313. https://doi.org/10.1155/2017/9295313
Koide M, Kobayashi Y (2018) Regulatory mechanisms of sclerostin expression during bone remodeling. J Bone Miner Metab. https://doi.org/10.1007/s00774-018-0971-7
Zhang L, Ouyang H, Xie Z, Liang ZH, Wu XW (2016) Serum DKK-1 level in the development of ankylosing spondylitis and rheumatic arthritis: a meta-analysis. Exp Mol Med 48:e228. https://doi.org/10.1038/emm.2016.12
Zou YC, Yang XW, Yuan SG, Zhang P, Ye YL, Li YK (2016) Downregulation of dickkopf-1 enhances the proliferation and osteogenic potential of fibroblasts isolated from ankylosing spondylitis patients via the Wnt/beta-catenin signaling pathway in vitro. Connect Tissue Res 57(3):200–211. https://doi.org/10.3109/03008207.2015.1127916
Wu M, Chen M, Ma Y, Yang J, Han R, Yuan Y, Hu X, Wang M, Zhang X, Xu S, Liu R, Jiang G, Xu J, Shuai Z, Zou Y, Pan G, Pan F (2018) Dickkopf-1 in ankylosing spondylitis: Review and meta-analysis. Clin Chim Acta 481:177–183. https://doi.org/10.1016/j.cca.2018.03.010
Diarra D, Stolina M, Polzer K, Zwerina J, Ominsky MS, Dwyer D, Korb A, Smolen J, Hoffmann M, Scheinecker C, van der Heide D, Landewe R, Lacey D, Richards WG, Schett G (2007) Dickkopf-1 is a master regulator of joint remodeling. Nat Med 13(2):156–163. https://doi.org/10.1038/nm1538
Kuipers AL, Zhang Y, Yu S, Kammerer CM, Nestlerode CS, Chu Y, Bunker CH, Patrick AL, Wheeler VW, Miljkovic I, Zmuda JM (2014) Relative influence of heritability, environment and genetics on serum sclerostin. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. Osteoporos Int 25 (3):905–912. https://doi.org/10.1007/s00198-013-2517-0
Luchetti MM, Ciccia F, Avellini C, Benfaremo D, Guggino G, Farinelli A, Ciferri M, Rossini M, Svegliati S, Spadoni T, Bolognini L, Fava G, Mosca P, Gesuita R, Skrami E, Triolo G, Gabrielli A (2018) Sclerostin and antisclerostin antibody serum levels predict the presence of axial spondyloarthritis in patients with inflammatory bowel disease. J Rheumatol 45(5):630–637. https://doi.org/10.3899/jrheum.170833
Pietrzyk B, Wyskida K, Ficek J, Kolonko A, Ficek R, Wiecek A, Olszanecka-Glinianowicz M, Chudek J (2018) Relationship between plasma levels of sclerostin, calcium-phosphate disturbances, established markers of bone turnover, and inflammation in haemodialysis patients. Int Urol Nephrol. https://doi.org/10.1007/s11255-018-2050-3
Almroth G, Lonn J, Uhlin F, Brudin L, Andersson B, Hahn-Zoric M (2016) Sclerostin, TNF-alpha and Interleukin-18 correlate and are together with Klotho related to other growth factors and cytokines in haemodialysis patients. Scand J Immunol 83(1):58–63. https://doi.org/10.1111/sji.12392
Croft M, Siegel RM (2017) Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases. Nat Rev Rheumatol 13(4):217–233. https://doi.org/10.1038/nrrheum.2017.22
Li SS (2017) Mechanisms underlying the post-transcriptional regulation of murine sclerostin by TNF-alpha. Thesis of master, Shandong university
Calin A, Garrett S, Whitelock H, Kennedy LG, O’Hea J, Mallorie P, Jenkinson T (1994) A new approach to defining functional ability in ankylosing spondylitis: the development of the Bath Ankylosing Spondylitis Functional Index. J Rheumatol 21(12):2281–2285
Li Q, Li L, Bi L, Xiao C, Lin Z, Cao S, Liao Z, Gu J (2016) Kunxian capsules in the treatment of patients with ankylosing spondylitis: a randomized placebo-controlled clinical trial. Trials 17(1):337. https://doi.org/10.1186/s13063-016-1438-6
Zong HX, Xu SQ, Tong H, Wang XR, Pan MJ, Teng YZ (2018) Effect of anti-tumor necrosis factor alpha treatment on radiographic progression in patient with ankylosing spondylitis: a systematic review and meta-analysis. Mod Rheumatol. https://doi.org/10.1080/14397595.2018.1525017
Muntean L, Lungu A, Gheorghe SR, Valeanu M, Craciun AM, Felea I, Petcu A, Filipescu I, Simon SP, Rednic S (2016) Elevated serum levels of sclerostin are associated with high disease activity and functional impairment in patients with axial spondyloarthritis. Clin Lab 62(4):589–597
Durosier C, van Lierop A, Ferrari S, Chevalley T, Papapoulos S, Rizzoli R (2013) Association of circulating sclerostin with bone mineral mass, microstructure, and turnover biochemical markers in healthy elderly men and women. J Clin Endocrinol Metab 98(9):3873–3883. https://doi.org/10.1210/jc.2013-2113
Piec I, Washbourne C, Tang J, Fisher E, Greeves J, Jackson S, Fraser WD (2016) How accurate is your sclerostin measurement? Comparison between three commercially available sclerostin ELISA kits. Calcif Tissue Int 98(6):546–555. https://doi.org/10.1007/s00223-015-0105-3
Liu Y, Hou R, Yin R, Yin W (2015) Correlation of bone morphogenetic protein-2 levels in serum and synovial fluid with disease severity of knee osteoarthritis. Med Sci Monit. 21:363–370. https://doi.org/10.12659/msm.892160
Chemel M, Brion R, Segaliny AI, Lamora A, Charrier C, Brulin B, Maugars Y, Le Goff B, Heymann D, Verrecchia F (2017) Bone morphogenetic protein 2 and transforming growth factor beta1 inhibit the expression of the proinflammatory cytokine IL-34 in rheumatoid arthritis synovial fibroblasts. Am J Pathol 187(1):156–162. https://doi.org/10.1016/j.ajpath.2016.09.015
Creemers MC, Franssen MJ, van’t Hof MA, Gribnau FW, van de Putte LB, van Riel PL (2005) Assessment of outcome in ankylosing spondylitis: an extended radiographic scoring system. Ann Rheum Dis 64(1):127–129. https://doi.org/10.1136/ard.2004.020503
Deminger A, Klingberg E, Geijer M, Gothlin J, Hedberg M, Rehnberg E, Carlsten H, Jacobsson LT, Forsblad-d’Elia H (2018) A five-year prospective study of spinal radiographic progression and its predictors in men and women with ankylosing spondylitis. Arthritis Res Therapy 20(1):162. https://doi.org/10.1186/s13075-018-1665-1
Ramiro S, Landewe R, van Tubergen A, Boonen A, Stolwijk C, Dougados M, van den Bosch F, van der Heijde D (2015) Lifestyle factors may modify the effect of disease activity on radiographic progression in patients with ankylosing spondylitis: a longitudinal analysis. RMD Open 1(1):e000153. https://doi.org/10.1136/rmdopen-2015-000153
Maas F, Arends S, Wink FR, Bos R, Bootsma H, Brouwer E, Spoorenberg A (2017) Ankylosing spondylitis patients at risk of poor radiographic outcome show diminishing spinal radiographic progression during long-term treatment with TNF-alpha inhibitors. PloS ONE 12(6):e0177231. https://doi.org/10.1371/journal.pone.0177231
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This study was supported by Grants from the National Natural Science Foundation of China (30972530, 81273169, 81573218 and 81773514).
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This study was funded by grants from the National Natural Science Foundation of China (30972530, 81273169, 81573218 and 81773514).
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Corresponding author Faming Pan came up with the idea and he is guarantor. Authors #a and #b performed the literature search. Author #c was responsible for statistical analysis. Author Jiajia Yang wrote the first draft of the article. Author #d and #e modified the manuscript. All authors reviewed the paper and approved the final version. All authors agree to be accountable for the work and to ensure that any questions relating to the accuracy and integrity of the paper are investigated and properly resolved.
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Jiajia Yang, Shanshan Xu, Mengya Chen, Yaping Yuan, Xu Zhang, Yubo Ma, Meng Wu, Renfang Han, Xingxing Hu, Rui Liu, Jixiang Deng, Shiyang Guan, Xing Gao, Meijuan Pan, Shengqian Xu, Zongwen Shuai, Shanqun Jiang, Shihe Guan, Liwen Chen, and Faming Pan declare they have no conflicts of interest.
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Yang, J., Xu, S., Chen, M. et al. Serum Sclerostin and Bone Morphogenetic Protein-2 Levels in Patients with Ankylosing Spondylitis: A Meta-Analysis. Calcif Tissue Int 105, 37–50 (2019). https://doi.org/10.1007/s00223-019-00542-z
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DOI: https://doi.org/10.1007/s00223-019-00542-z