Ankilozan Spondilitli Hastalarda Serum High Mobility Group Box-1 (HMGB1) Düzeylerinin Hastalık Aktivitesi, Kemik Mineral Yoğunluğu ve RANKL/Osteoprotegerin Aksı ile İlişkisi

Öz

Amaç: High mobility group box-1 (HMGB1), enflamasyondaki rolünün yanı sıra, reseptör aktivatör nükleer faktör κB ligandın (RANKL) indüklediği osteoklastogenezisi düzenler. Bu çalışmanın amacı, ankilozan spondilit (AS) hastalarında serum HMGB1 düzeylerinin hastalık aktivitesi, kemik mineral yoğunluğu (KMY) ve RANKL/osteoprotegerin (OPG) aksı ile ilişkisini araştırmaktır. Gereç ve Yöntemler: Bu çalışmaya 61 AS hastası ve hasta grubu ile yaş/cinsiyet olarak eşleştirilmiş 25 sağlıklı kontrol alındı. Hastalık ile ilişkili özellikler, Bath Ankilozan Spondilit Metroloji İndeksi ve Bath Ankilozan Spondilit Fonksiyonel İndeksi skorları ile eritrosit sedimantasyon hızı (ESH) ve C-reaktif protein (CRP) düzeyleri kaydedildi. Hastalık aktivitesini değerlendirmek için Bath Ankilozan Spondilit Aktivite İndeksi (BASDAI) ve Ankilozan Spondilit Hastalık Aktivite Skoru (ASDAS)-CRP kullanıldı. KMY, lomber omurga ve proksimal femurdan dual enerji X-ray absorpsiyometri kullanılarak ölçüldü. Serum HMGB1, RANKL ve OPG düzeyleri ticari ELISA kitleri kullanılarak ölçüldü. Bulgular: HMGB1 düzeyleri AS hastaları ve sağlıklı kontroller arasında benzerdi. AS hastalarında kontrol grubuna göre RANKL düzeyleri anlamlı olarak yüksek (p = 0.006) ve OPG düzeyleri anlamlı olarak düşüktü (p = 0.002). AS hastalarında HMGB1 düzeyleri ile CRP (r = 0.424, p = 0.001), ASDAS-CRP (r = 0.329, p = 0.010) ve BASDAI (r = 0.288, p = 0.024) arasında anlamlı korelasyonlar bulundu. HMGB1 düzeyleri ile RANKL ve OPG düzeyleri ve KMY ölçümleri arasında ise anlamlı bir ilişki yoktu. Sonuç: Bu çalışma, serum HMGB1 düzeylerinin AS'deki hastalık aktivitesi ile ilişkili olduğunu göstererek, HMGB1'in AS patogenezinde rol oynadığı hipotezini desteklemektedir. Bununla birlikte, AS'de serum HMGB1 düzeyleri RANKL-OPG aksı veya KMY ile ilişkili değildi.

Anahtar Kelimeler

• Ankilozan spondilit
• High-mobility group box 1 (HMGB1)
• RANKL
• Osteoprotegerin
• Osteoporoz

Kaynakça

1. Klavdianou K, Tsiami S, Baraliakos X. New developments in ankylosing spondylitis-status in 2021. Rheumatology (Oxford). 2021;60(Suppl 6):vi29-vi37.
2. Mauro D, Thomas R, Guggino G, Lories R, Brown MA, Ciccia F. Ankylosing spondylitis: an autoimmune or autoinflammatory disease? Nat Rev Rheumatol. 2021;17(7):387-404.
3. Singh HJ, Nimarpreet K, Ashima, Das S, Kumar A, Prakash S. Study of bone mineral density in patients with ankylosing spondylitis. J Clin Diagn Res. 2013;7(12):2832-5.
4. Klingberg E, Lorentzon M, Göthlin J, Mellström D, Geijer M, Ohlsson C, et al. Bone microarchitecture in ankylosing spondylitis and the association with bone mineral density, fractures, and syndesmophytes. Arthritis Res Ther. 2013;15(6):R179.
5. Magrey M, Khan MA. Osteoporosis in ankylosing spondylitis. Curr Rheumatol Rep. 2010;12(5):332-6.
6. Boyce BF, Xing L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys. 2008;473(2):139-46.
7. Kim HR, Lee SH, Kim HY. Elevated serum levels of soluble receptor activator of nuclear factors-kappaB ligand (sRANKL) and reduced bone mineral density in patients with ankylosing spondylitis (AS). Rheumatology (Oxford). 2006;45(10):1197-200.
8. Klingberg E, Nurkkala M, Carlsten H, Forsblad-d'Elia H. Biomarkers of bone metabolism in ankylosing spondylitis in relation to osteoproliferation and osteoporosis. J Rheumatol. 2014;41(7):1349-56.

9. Ni F, Zhang Y, Peng Y, Peng X, Li J. Serum RANKL levels in Chinese patients with ankylosing spondylitis: a meta-analysis. J Orthop Surg Res. 2021;16(1):615.
10. Chen M, Hu X, Wu M, Yang J, Han R, Ma Y, et al. Serum Levels of OPG, RANKL, and RANKL/OPG Ratio in Patients with Ankylosing Spondylitis: A Systematic Review and Meta-analysis. Immunol Invest. 2019;48(5):490-504.
11. Kang R, Chen R, Zhang Q, Hou W, Wu S, Cao L, et al. HMGB1 in health and disease. Mol Aspects Med. 2014;40:1-116.
12. Yang H, Wang H, Andersson U. Targeting Inflammation Driven by HMGB1. Front Immunol. 2020;11:484.
13. Oktayoglu P, Em S, Tahtasiz M, Bozkurt M, Ucar D, Yazmalar L, et al. Elevated serum levels of high mobility group box protein 1 (HMGB1) in patients with ankylosing spondylitis and its association with disease activity and quality of life. Rheumatol Int. 2013;33(5):1327-31.
14. Chen Y, Sun W, Li S, Ni J, Su Y, Wang C, et al. Preliminary study of high mobility group box chromosomal protein 1(HMGB1) in ankylosing spondylitis patients. Clin Exp Rheumatol. 2015;33(2):187-94.
15. Wang C, Miao Y, Wu X, Huang Y, Sun M, Zhu Y, et al. Serum HMGB1 Serves as a Novel Laboratory Indicator Reflecting Disease Activity and Treatment Response in Ankylosing Spondylitis Patients. J Immunol Res. 2016;2016:6537248.
16. Dong Y, Ming B, Dong L. The Role of HMGB1 in Rheumatic Diseases. Front Immunol. 2022;13:815257.
17. Zhou Z, Han JY, Xi CX, Xie JX, Feng X, Wang CY, et al. HMGB1 regulates RANKL-induced osteoclastogenesis in a manner dependent on RAGE. J Bone Miner Res. 2008;23(7):1084-96.
18. Hou C, Luan L, Ren C. Oxidized low-density lipoprotein promotes osteoclast differentiation from CD68 positive mononuclear cells by regulating HMGB1 release. Biochem Biophys Res Commun. 2018;495(1):1356-62.
19. Akkoc Y, Karatepe AG, Akar S, Kirazli Y, Akkoc N. A Turkish version of the Bath Ankylosing Spondylitis Disease Activity Index: reliability and validity. Rheumatol Int. 2005;25(4):280-4.
20. van der Heijde D, Lie E, Kvien TK, Sieper J, Van den Bosch F, Listing J, et al. ASDAS, a highly discriminatory ASAS-endorsed disease activity score in patients with ankylosing spondylitis. Ann Rheum Dis. 2009;68(12):1811-8.
21. Jenkinson TR, Mallorie PA, Whitelock HC, Kennedy LG, Garrett SL, Calin A. Defining spinal mobility in ankylosing spondylitis (AS). The Bath AS Metrology Index. J Rheumatol. 1994;21(9):1694-8.
22. Yanik B, Gürsel YK, Kutlay S, Ay S, Elhan AH. Adaptation of the Bath Ankylosing Spondylitis Functional Index to the Turkish population, its reliability and validity: functional assessment in AS. Clin Rheumatol. 2005;24(1):41-7.
23. 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.
24. Kuroiwa Y, Takakusagi Y, Kusayanagi T, Kuramochi K, Imai T, Hirayama T, et al. Identification and characterization of the direct interaction between methotrexate (MTX) and high-mobility group box 1 (HMGB1) protein. PLoS One. 2013;8(5):e63073.
25. Li L, Liu M, Zhang T, Jia Y, Zhang Y, Yuan H, et al. Indomethacin down-regulating HMGB1 and TNF-α to prevent pancreatitis after endoscopic retrograde cholangiopancreatography. Scand J Gastroenterol. 2019;54(6):793-9.
26. Chen CH, Chen HA, Liao HT, Liu CH, Tsai CY, Chou CT. 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. Clin Rheumatol. 2010;29(10):1155-61.
27. Taylan A, Sari I, Akinci B, Bilge S, Kozaci D, Akar S, et al. Biomarkers and cytokines of bone turnover: extensive evaluation in a cohort of patients with ankylosing spondylitis. BMC Musculoskelet Disord. 2012;13:191.
28. Bidwell JP, Yang J, Robling AG. Is HMGB1 an osteocyte alarmin? J Cell Biochem. 2008;103(6):1671-80.
29. Li Z, Chen C, Zhu X, Li Y, Yu R, Xu W. Glycyrrhizin Suppresses RANKL-Induced Osteoclastogenesis and Oxidative Stress Through Inhibiting NF-κB and MAPK and Activating AMPK/Nrf2. Calcif Tissue Int. 2018;103(3):324-37.
30. Li ZC, Cheng GQ, Hu KZ, Li MQ, Zang WP, Dong YQ, et al. Correlation of synovial fluid HMGB-1 levels with radiographic severity of knee osteoarthritis. Clin Invest Med. 2011;34(5):E298.
31. Hu X, Chen J, Tang W, Chen W, Sang Y, Jia L. Effects of exercise programmes on pain, disease activity and function in ankylosing spondylitis: A meta-analysis of randomized controlled trials. Eur J Clin Invest. 2020;50(12):e13352.