Serum Galectin-3 Level in Patients with Rheumatoid Arthritis: A Systematic Review and Meta-analysis
-
Mehrdad Mahalleh
,
Amir Hossein Behnoush
,
Amirmohammad Khalaji
,
Mahdi Gouravani
,
Ramin Assempoor
,
Ahmadreza Jamshidi
,
Mahdi Mahmoudi
,
Elham Farhadi
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial tissue transformation and fibroblast-like synoviocyte (FLS) proliferation. Galectin-3 is gaining attention as a diagnostic and prognostic biomarker for RA diagnosis. Elevated levels of Galectin-3 cause RA-FLSs to stimulate and generate proinflammatory agents, contributing to cartilage degradation and osteoclast formation. This systematic review and meta-analysis aimed to evaluate published evidence and support future investigation of Galectin-3 as an early biomarker for RA.
A systematic search was performed through four databases, including PubMed, the Web of Science, Scopus, and Embase, to find the studies examining Galectin-3 in individuals with RA compared to healthy controls. The risk of bias was evaluated using the Newcastle-Ottawa Quality Assessment Scale. Random-effects meta-analysis comparing serum/plasma Galectin-3 levels between individuals with RA and healthy control groups was performed to determine the standardized mean differences (SMD) along with 95% confidence intervals.
Following the initial search, studies went through screening. 12 studies, involving 773 patients with RA and 411 healthy controls, were included. Meta-analysis of the included studies revealed that individuals with RA had significantly higher levels of circulatory Galectin-3 compared to healthy control groups (SMD 0.957, 95% CI 0.393 to 1.520). Univariable meta-regression showed no significant association between age, publication year, sample size, or the male percentage with effect size.
According to the results, Galectin-3 might be useful as a biomarker for RA. To support these findings, further investigations of Galectin-3 as a possible early biomarker of RA is necessary.
1. Black RJ, Cross M, Haile LM, Culbreth GT, Steinmetz JD, Hagins H, et al. Global, regional, and national burden of rheumatoid arthritis, 1990–2020, and projections to 2050: a systematic analysis of the Global Burden of Disease Study 2021. The Lancet Rheumatology. 2023;5(10):e594-e610.
2. Mahmoud DE, Kaabachi W, Sassi N, Tarhouni L, Rekik S, Jemmali S, et al. The synovial fluid fibroblast-like synoviocyte: A long-neglected piece in the puzzle of rheumatoid arthritis pathogenesis. Front Immunol. 2022;13:942417.
3. Maximilian K, Mirjam D, Felix K, Lena M, Teresa P, Leonhard XH, et al. Cytokine-directed cellular cross-talk imprints synovial pathotypes in rheumatoid arthritis. Annals of the Rheumatic Diseases. 2023;82(9):1142.
4. Kronzer VL, Crowson CS, Sparks JA, Myasoedova E, Davis JM, 3rd. Comorbidities As Risk Factors for Rheumatoid Arthritis and Their Accrual After Diagnosis. Mayo Clin Proc. 2019;94(12):2488-98.
5. Nagy G, Roodenrijs NMT, Welsing PMJ, Kedves M, Hamar A, van der Goes MC, et al. EULAR points to consider for the management of difficult-to-treat rheumatoid arthritis. Ann Rheum Dis. 2022;81(1):20-33.
6. Shapiro SC. Biomarkers in Rheumatoid Arthritis. Cureus. 2021;13(5):e15063.
7. Hirabayashi J, Kasai K. The family of metazoan metal-independent beta-galactoside-binding lectins: structure, function and molecular evolution. Glycobiology. 1993;3(4):297-304.
8. Sciacchitano S, Lavra L, Morgante A, Ulivieri A, Magi F, De Francesco GP, et al. Galectin-3: One Molecule for an Alphabet of Diseases, from A to Z. Int J Mol Sci. 2018;19(2).
9. Dong R, Zhang M, Hu Q, Zheng S, Soh A, Zheng Y, et al. Galectin-3 as a novel biomarker for disease diagnosis and a target for therapy (Review). Int J Mol Med. 2018;41(2):599-614.
10. Hu Y, Yéléhé-Okouma M, Ea H-K, Jouzeau J-Y, Reboul P. Galectin-3: A key player in arthritis. Joint Bone Spine. 2017;84(1):15-20.
11. Mendez-Huergo SP, Hockl PF, Stupirski JC, Maller SM, Morosi LG, Pinto NA, et al. Clinical Relevance of Galectin-1 and Galectin-3 in Rheumatoid Arthritis Patients: Differential Regulation and Correlation With Disease Activity. Front Immunol. 2018;9:3057.
12. Nielsen MA, Køster D, Greisen S, Troldborg A, Stengaard-Pedersen K, Junker P, et al. Increased synovial galectin-3 induce inflammatory fibroblast activation and osteoclastogenesis in patients with rheumatoid arthritis. Scandinavian Journal of Rheumatology. 2023;52(1):33-41.
13. Nakajima K, Kho DH, Yanagawa T, Harazono Y, Gao X, Hogan V, et al. Galectin-3 inhibits osteoblast differentiation through notch signaling. Neoplasia. 2014;16(11):939-49.
14. Forsman H, Islander U, Andréasson E, Andersson A, Onnheim K, Karlström A, et al. Galectin 3 aggravates joint inflammation and destruction in antigen-induced arthritis. Arthritis Rheum. 2011;63(2):445-54.
15. Shou J, Bull CM, Li L, Qian HR, Wei T, Luo S, et al. Identification of blood biomarkers of rheumatoid arthritis by transcript profiling of peripheral blood mononuclear cells from the rat collagen-induced arthritis model. Arthritis Res Ther. 2006;8(1):R28.
16. Li S, Yu Y, Koehn CD, Zhang Z, Su K. Galectins in the Pathogenesis of Rheumatoid Arthritis. J Clin Cell Immunol. 2013;4(5).
17. Filer A, Bik M, Parsonage GN, Fitton J, Trebilcock E, Howlett K, et al. Galectin 3 induces a distinctive pattern of cytokine and chemokine production in rheumatoid synovial fibroblasts via selective signaling pathways. Arthritis Rheum. 2009;60(6):1604-14.
18. Ohshima S, Kuchen S, Seemayer CA, Kyburz D, Hirt A, Klinzing S, et al. Galectin 3 and its binding protein in rheumatoid arthritis. Arthritis Rheum. 2003;48(10):2788-95.
19. Janelle-Montcalm A, Boileau C, Poirier F, Pelletier JP, Guévremont M, Duval N, et al. Extracellular localization of galectin-3 has a deleterious role in joint tissues. Arthritis Res Ther. 2007;9(1):R20.
20. Gruszewska E, Cylwik B, Gińdzieńska-Sieśkiewicz E, Kowal-Bielecka O, Mroczko B, Chrostek L. Diagnostic Power of Galectin-3 in Rheumatic Diseases. J Clin Med. 2020;9(10).
21. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.
22. Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Oxford; 2000.
23. Luo D, Wan X, Liu J, Tong T. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res. 2018;27(6):1785-805.
24. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014;14:135.
25. Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane handbook for systematic reviews of interventions: John Wiley & Sons; 2019.
26. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. Bmj. 1997;315(7109):629-34.
27. Andonian BJ, Bartlett DB, Huebner JL, Willis L, Hoselton A, Kraus VB, et al. Effect of high-intensity interval training on muscle remodeling in rheumatoid arthritis compared to prediabetes. Arthritis Res Ther. 2018;20(1):283.
28. Anyfanti P, Gkaliagkousi E, Gavriilaki E, Triantafyllou A, Dolgyras P, Galanopoulou V, et al. Association of galectin-3 with markers of myocardial function, atherosclerosis, and vascular fibrosis in patients with rheumatoid arthritis. Clin Cardiol. 2019;42(1):62-8.
29. Anyfanti P, Dimitriadou A, Dara A, Angeloudi E, Gavriilaki E, Nikolaidou B, et al. Circulating levels of galectin-3 and coronary microvascular perfusion in rheumatoid arthritis patients with suppressed inflammation. Clin Rheumatol. 2023;42(10):2881-7.
30. Issa SF, Christensen AF, Lottenburger T, Junker K, Lindegaard H, Hørslev-Petersen K, et al. Within-day variation and influence of physical exercise on circulating Galectin-3 in patients with rheumatoid arthritis and healthy individuals. Scand J Immunol. 2015;82(1):70-5.
31. Issa SF, Christensen AF, Lindegaard HM, Hetland ML, Hørslev-Petersen K, Stengaard-Pedersen K, et al. Galectin-3 is Persistently Increased in Early Rheumatoid Arthritis (RA) and Associates with Anti-CCP Seropositivity and MRI Bone Lesions, While Early Fibrosis Markers Correlate with Disease Activity. Scand J Immunol. 2017;86(6):471-8.
32. Nussdorf A, Park E, Amigues I, Geraldino-Pardilla L, Bokhari S, Giles JT, et al. Associations of galectin-3 levels with measures of vascular disease in patients with rheumatoid arthritis. Semin Arthritis Rheum. 2024;65:152357.
33. Pedersen K, Nielsen MA, Juul-Madsen K, Hvid M, Deleuran B, Greisen SR. Galectin-3 interacts with PD-1 and counteracts the PD-1 pathway-driven regulation of T cell and osteoclast activity in Rheumatoid Arthritis. Scand J Immunol. 2023;97(2):e13245.
34. Lee YJ, Kang SW, Song JK, Park JJ, Bae YD, Lee EY, et al. Serum galectin-3 and galectin-3 binding protein levels in Behçet's disease and their association with disease activity. Clin Exp Rheumatol. 2007;25(4 Suppl 45):S41-5.
35. Blanda V, Bracale UM, Di Taranto MD, Fortunato G. Galectin-3 in Cardiovascular Diseases. International Journal of Molecular Sciences [Internet]. 2020; 21(23).
36. Ahmed R, Anam K, Ahmed H. Development of Galectin-3 Targeting Drugs for Therapeutic Applications in Various Diseases. International Journal of Molecular Sciences [Internet]. 2023; 24(9).
37. Xue S, Lozinski BM, Ghorbani S, Ta K, D'Mello C, Yong VW, et al. Elevated Galectin-3 Is Associated with Aging, Multiple Sclerosis, and Oxidized Phosphatidylcholine-Induced Neurodegeneration. J Neurosci. 2023;43(25):4725-37.
38. Li LC, Li J, Gao J. Functions of galectin-3 and its role in fibrotic diseases. J Pharmacol Exp Ther. 2014;351(2):336-43.
39. de Oliveira FL, Gatto M, Bassi N, Luisetto R, Ghirardello A, Punzi L, et al. Galectin-3 in autoimmunity and autoimmune diseases. Exp Biol Med (Maywood). 2015;240(8):1019-28.
40. Chen HY, Liu FT, Yang RY. Roles of galectin-3 in immune responses. Arch Immunol Ther Exp (Warsz). 2005;53(6):497-504.
41. Neidhart M, Zaucke F, von Knoch R, Jüngel A, Michel BA, Gay RE, et al. Galectin-3 is induced in rheumatoid arthritis synovial fibroblasts after adhesion to cartilage oligomeric matrix protein. Ann Rheum Dis. 2005;64(3):419-24.
42. Vuong L, Kouverianou E, Rooney CM, McHugh BJ, Howie SEM, Gregory CD, et al. An Orally Active Galectin-3 Antagonist Inhibits Lung Adenocarcinoma Growth and Augments Response to PD-L1 Blockade. Cancer Res. 2019;79(7):1480-92.
43. Iurisci I, Tinari N, Natoli C, Angelucci D, Cianchetti E, Iacobelli S. Concentrations of galectin-3 in the sera of normal controls and cancer patients. Clin Cancer Res. 2000;6(4):1389-93.
44. Farhad M, Rolig AS, Redmond WL. The role of Galectin-3 in modulating tumor growth and immunosuppression within the tumor microenvironment. Oncoimmunology. 2018;7(6):e1434467.
45. Suthahar N, Lau ES, Blaha MJ, Paniagua SM, Larson MG, Psaty BM, et al. Sex-Specific Associations of Cardiovascular Risk Factors and Biomarkers With Incident Heart Failure. J Am Coll Cardiol. 2020;76(12):1455-65.
2. Mahmoud DE, Kaabachi W, Sassi N, Tarhouni L, Rekik S, Jemmali S, et al. The synovial fluid fibroblast-like synoviocyte: A long-neglected piece in the puzzle of rheumatoid arthritis pathogenesis. Front Immunol. 2022;13:942417.
3. Maximilian K, Mirjam D, Felix K, Lena M, Teresa P, Leonhard XH, et al. Cytokine-directed cellular cross-talk imprints synovial pathotypes in rheumatoid arthritis. Annals of the Rheumatic Diseases. 2023;82(9):1142.
4. Kronzer VL, Crowson CS, Sparks JA, Myasoedova E, Davis JM, 3rd. Comorbidities As Risk Factors for Rheumatoid Arthritis and Their Accrual After Diagnosis. Mayo Clin Proc. 2019;94(12):2488-98.
5. Nagy G, Roodenrijs NMT, Welsing PMJ, Kedves M, Hamar A, van der Goes MC, et al. EULAR points to consider for the management of difficult-to-treat rheumatoid arthritis. Ann Rheum Dis. 2022;81(1):20-33.
6. Shapiro SC. Biomarkers in Rheumatoid Arthritis. Cureus. 2021;13(5):e15063.
7. Hirabayashi J, Kasai K. The family of metazoan metal-independent beta-galactoside-binding lectins: structure, function and molecular evolution. Glycobiology. 1993;3(4):297-304.
8. Sciacchitano S, Lavra L, Morgante A, Ulivieri A, Magi F, De Francesco GP, et al. Galectin-3: One Molecule for an Alphabet of Diseases, from A to Z. Int J Mol Sci. 2018;19(2).
9. Dong R, Zhang M, Hu Q, Zheng S, Soh A, Zheng Y, et al. Galectin-3 as a novel biomarker for disease diagnosis and a target for therapy (Review). Int J Mol Med. 2018;41(2):599-614.
10. Hu Y, Yéléhé-Okouma M, Ea H-K, Jouzeau J-Y, Reboul P. Galectin-3: A key player in arthritis. Joint Bone Spine. 2017;84(1):15-20.
11. Mendez-Huergo SP, Hockl PF, Stupirski JC, Maller SM, Morosi LG, Pinto NA, et al. Clinical Relevance of Galectin-1 and Galectin-3 in Rheumatoid Arthritis Patients: Differential Regulation and Correlation With Disease Activity. Front Immunol. 2018;9:3057.
12. Nielsen MA, Køster D, Greisen S, Troldborg A, Stengaard-Pedersen K, Junker P, et al. Increased synovial galectin-3 induce inflammatory fibroblast activation and osteoclastogenesis in patients with rheumatoid arthritis. Scandinavian Journal of Rheumatology. 2023;52(1):33-41.
13. Nakajima K, Kho DH, Yanagawa T, Harazono Y, Gao X, Hogan V, et al. Galectin-3 inhibits osteoblast differentiation through notch signaling. Neoplasia. 2014;16(11):939-49.
14. Forsman H, Islander U, Andréasson E, Andersson A, Onnheim K, Karlström A, et al. Galectin 3 aggravates joint inflammation and destruction in antigen-induced arthritis. Arthritis Rheum. 2011;63(2):445-54.
15. Shou J, Bull CM, Li L, Qian HR, Wei T, Luo S, et al. Identification of blood biomarkers of rheumatoid arthritis by transcript profiling of peripheral blood mononuclear cells from the rat collagen-induced arthritis model. Arthritis Res Ther. 2006;8(1):R28.
16. Li S, Yu Y, Koehn CD, Zhang Z, Su K. Galectins in the Pathogenesis of Rheumatoid Arthritis. J Clin Cell Immunol. 2013;4(5).
17. Filer A, Bik M, Parsonage GN, Fitton J, Trebilcock E, Howlett K, et al. Galectin 3 induces a distinctive pattern of cytokine and chemokine production in rheumatoid synovial fibroblasts via selective signaling pathways. Arthritis Rheum. 2009;60(6):1604-14.
18. Ohshima S, Kuchen S, Seemayer CA, Kyburz D, Hirt A, Klinzing S, et al. Galectin 3 and its binding protein in rheumatoid arthritis. Arthritis Rheum. 2003;48(10):2788-95.
19. Janelle-Montcalm A, Boileau C, Poirier F, Pelletier JP, Guévremont M, Duval N, et al. Extracellular localization of galectin-3 has a deleterious role in joint tissues. Arthritis Res Ther. 2007;9(1):R20.
20. Gruszewska E, Cylwik B, Gińdzieńska-Sieśkiewicz E, Kowal-Bielecka O, Mroczko B, Chrostek L. Diagnostic Power of Galectin-3 in Rheumatic Diseases. J Clin Med. 2020;9(10).
21. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.
22. Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Oxford; 2000.
23. Luo D, Wan X, Liu J, Tong T. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res. 2018;27(6):1785-805.
24. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014;14:135.
25. Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane handbook for systematic reviews of interventions: John Wiley & Sons; 2019.
26. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. Bmj. 1997;315(7109):629-34.
27. Andonian BJ, Bartlett DB, Huebner JL, Willis L, Hoselton A, Kraus VB, et al. Effect of high-intensity interval training on muscle remodeling in rheumatoid arthritis compared to prediabetes. Arthritis Res Ther. 2018;20(1):283.
28. Anyfanti P, Gkaliagkousi E, Gavriilaki E, Triantafyllou A, Dolgyras P, Galanopoulou V, et al. Association of galectin-3 with markers of myocardial function, atherosclerosis, and vascular fibrosis in patients with rheumatoid arthritis. Clin Cardiol. 2019;42(1):62-8.
29. Anyfanti P, Dimitriadou A, Dara A, Angeloudi E, Gavriilaki E, Nikolaidou B, et al. Circulating levels of galectin-3 and coronary microvascular perfusion in rheumatoid arthritis patients with suppressed inflammation. Clin Rheumatol. 2023;42(10):2881-7.
30. Issa SF, Christensen AF, Lottenburger T, Junker K, Lindegaard H, Hørslev-Petersen K, et al. Within-day variation and influence of physical exercise on circulating Galectin-3 in patients with rheumatoid arthritis and healthy individuals. Scand J Immunol. 2015;82(1):70-5.
31. Issa SF, Christensen AF, Lindegaard HM, Hetland ML, Hørslev-Petersen K, Stengaard-Pedersen K, et al. Galectin-3 is Persistently Increased in Early Rheumatoid Arthritis (RA) and Associates with Anti-CCP Seropositivity and MRI Bone Lesions, While Early Fibrosis Markers Correlate with Disease Activity. Scand J Immunol. 2017;86(6):471-8.
32. Nussdorf A, Park E, Amigues I, Geraldino-Pardilla L, Bokhari S, Giles JT, et al. Associations of galectin-3 levels with measures of vascular disease in patients with rheumatoid arthritis. Semin Arthritis Rheum. 2024;65:152357.
33. Pedersen K, Nielsen MA, Juul-Madsen K, Hvid M, Deleuran B, Greisen SR. Galectin-3 interacts with PD-1 and counteracts the PD-1 pathway-driven regulation of T cell and osteoclast activity in Rheumatoid Arthritis. Scand J Immunol. 2023;97(2):e13245.
34. Lee YJ, Kang SW, Song JK, Park JJ, Bae YD, Lee EY, et al. Serum galectin-3 and galectin-3 binding protein levels in Behçet's disease and their association with disease activity. Clin Exp Rheumatol. 2007;25(4 Suppl 45):S41-5.
35. Blanda V, Bracale UM, Di Taranto MD, Fortunato G. Galectin-3 in Cardiovascular Diseases. International Journal of Molecular Sciences [Internet]. 2020; 21(23).
36. Ahmed R, Anam K, Ahmed H. Development of Galectin-3 Targeting Drugs for Therapeutic Applications in Various Diseases. International Journal of Molecular Sciences [Internet]. 2023; 24(9).
37. Xue S, Lozinski BM, Ghorbani S, Ta K, D'Mello C, Yong VW, et al. Elevated Galectin-3 Is Associated with Aging, Multiple Sclerosis, and Oxidized Phosphatidylcholine-Induced Neurodegeneration. J Neurosci. 2023;43(25):4725-37.
38. Li LC, Li J, Gao J. Functions of galectin-3 and its role in fibrotic diseases. J Pharmacol Exp Ther. 2014;351(2):336-43.
39. de Oliveira FL, Gatto M, Bassi N, Luisetto R, Ghirardello A, Punzi L, et al. Galectin-3 in autoimmunity and autoimmune diseases. Exp Biol Med (Maywood). 2015;240(8):1019-28.
40. Chen HY, Liu FT, Yang RY. Roles of galectin-3 in immune responses. Arch Immunol Ther Exp (Warsz). 2005;53(6):497-504.
41. Neidhart M, Zaucke F, von Knoch R, Jüngel A, Michel BA, Gay RE, et al. Galectin-3 is induced in rheumatoid arthritis synovial fibroblasts after adhesion to cartilage oligomeric matrix protein. Ann Rheum Dis. 2005;64(3):419-24.
42. Vuong L, Kouverianou E, Rooney CM, McHugh BJ, Howie SEM, Gregory CD, et al. An Orally Active Galectin-3 Antagonist Inhibits Lung Adenocarcinoma Growth and Augments Response to PD-L1 Blockade. Cancer Res. 2019;79(7):1480-92.
43. Iurisci I, Tinari N, Natoli C, Angelucci D, Cianchetti E, Iacobelli S. Concentrations of galectin-3 in the sera of normal controls and cancer patients. Clin Cancer Res. 2000;6(4):1389-93.
44. Farhad M, Rolig AS, Redmond WL. The role of Galectin-3 in modulating tumor growth and immunosuppression within the tumor microenvironment. Oncoimmunology. 2018;7(6):e1434467.
45. Suthahar N, Lau ES, Blaha MJ, Paniagua SM, Larson MG, Psaty BM, et al. Sex-Specific Associations of Cardiovascular Risk Factors and Biomarkers With Incident Heart Failure. J Am Coll Cardiol. 2020;76(12):1455-65.
| Files | ||
| Issue | Vol 23 No 5 (2024) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v23i5.16777 | |
| Keywords | ||
| Inflammation Galectin-3 Rheumatic diseases Rheumatoid arthritis | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Mahalleh M, Behnoush A, Khalaji A, Gouravani M, Assempoor R, Jamshidi A, Mahmoudi M, Farhadi E. Serum Galectin-3 Level in Patients with Rheumatoid Arthritis: A Systematic Review and Meta-analysis. Iran J Allergy Asthma Immunol. 2024;23(5):476-488.
