Firdevs ULUTAŞ, Ozan ÇETİN, Veli ÇOBANKARA

Interleukin-23 receptor gene polymorphisms in osteoporosis

Objectives: Osteoporosis (OP) is a usual disease with a possible genetic predisposition. IL-23 plays a role in physiological bone remodeling and regulates the activity of cells of the bone either directly or indirectly on bone-resorbing osteoclasts as well as on bone-forming osteoblasts. Recent animal and human trials have revealed the main pro-osteoclastogenic activities for the IL-23 pathway. We examined nine single nucleotide polymorphisms (SNPs) in the interleukin-23 receptor (IL-23R) in 100 OP patients and gender- and age-matched 96 healthy volunteers. The most analyzed SNPs in the recent rheumatology literature were selected. Methods: In addition to gene polymorphisms several laboratory parameters (osteocalcin, parathormone, vitamine D) were investigated. Independent Samples t-test and Mann-Whitney-U test were used to compare several demographic and clinical parameters between the groups. P-value < 0.05 was accepted to be statistically significant. Results: Having the heterozygous GA genotype of IL-23R rs1004819 and the heterozygous CT genotype of Il-23R rs7530511 significantly increase the risk of developing OP (adjusted OR: 3.51, p = 0.031 and OR: 2.41, p = 0.027, respectively). The wild homozygous GG genotype of Il-23R rs11209032 had higher osteocalcin levels compared with the mutant homozygous AA genotype (18.75 ± 9.76, p = 0.009). Conclusions: Our findings suggest that several IL-23R gene polymorphisms are seen more often in osteoporosis patients than in healthy volunteers. In addition, some SNPs were related to higher serum osteocalcin levels.

Keywords:

Osteoporosis interleukin 23 receptor, gene polymorphisms, osteocalcin,

PDF

___

1. Lane JM, Russell L, Khan SN. Osteoporosis. Clin Orthop Relat Res 2000;372:139-50.
2. Floss DM, Schroder J, Franke M, Scheller J. Insights into IL-23 biology: from structure to function. Cytokine Growth Factor Rev 2015;26:569-78.
3. Razawy W, van Driel M, Lubberts E. The role of IL-23 receptor signaling in inflammation-mediated erosive autoimmune arthritis and bone remodeling. Eur J Immunol 2018;48:220-9.
4. Shin HS, Sarin R, Dixit N, Wu J, Gershwin E, Bowman EP, et al. Crosstalk among IL-23 and DNAX activating protein of 12 kDa-dependent pathways promotes osteoclastogenesis. J Immunol 2015;194:316-24.
5. Ju JH, Cho ML, Moon YM, Oh HJ, Park JS, Jhun JY, et al. IL-23 induces receptor activator of NF-kappa B ligand expression on CD4+ T cells and promotes osteoclastogenesis in an autoimmune arthritis model. J Immunol 2008;181:1507-18.
6. Chen L, Wei XQ, Evans B, Jiang W, Aeschlimann D. IL-23 promotes osteoclast formation by up-regulation of receptor activator of NF-kappa B (RANK) expression in myeloid precursor cells. Eur J Immunol 2008;38:2845-54.
7. Gravallese EM, Schett G. Effects of the IL-23-IL-17 pathway on bone in spondyloarthritis. Nat Rev Rheumatol 2018;14:631-40.
8. Shukla P, Mansoori MN, Singh D. Efficacy of anti-IL-23 monotherapy versus combination therapy with anti-IL-17 in estrogen deficiency-induced bone loss conditions. Bone 2018;110:84-95.
9. Razawy W, Alves CH, Koedam M, Asmawidjaja PS, Mus AMC, Oukka M, et al. IL-23 receptor deficiency results in lower bone mass via indirect regulation of bone formation. Sci Rep 2021;11:10244.
10. Quinn JM, Sims NA, Saleh H, Mirosa D, Thompson K, Bouralexis S, et al. IL-23 inhibits osteoclastogenesis indirectly through lymphocytes and is required for the maintenance of bone mass in mice. J Immunol 2008;181:5720-9.
11. Song GG, Bae SC, Choi SJ, Ji JD, Lee YH. Associations between interleukin-23 receptor polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis. Mol Biol Rep 2012;39:10655-63.
12. Huffmeier U, Lascorz J, Bohm B, Lohmann J, Wendler J, Mossner R, et al. Genetic variants of the IL-23R pathway: association with psoriatic arthritis and psoriasis vulgaris, but no specific risk factor for arthritis. J Invest Dermatol 2009;129:355-8.
13. Bridgewood C, Sharif K, Sherlock J, Watad A, McGonagle D. Interleukin-23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy. Immunol Rev 2020;294:27-47.
14. Kasamatsu T, Kimoto M, Takahashi N, Minato Y, Gotoh N, Takizawa M, et al. IL17A and IL23R gene polymorphisms affect the clinical features and prognosis of patients with multiple myeloma. Hematol Oncol 2018;36:196-201.
15. Kim TH, Hong JM, Oh B, Cho YS, Lee JY, Kim HL, et al. Association of polymorphisms in the Interleukin 23 receptor gene with osteonecrosis of the femoral head in the Korean population. Exp Mol Med 2008;40:418-26.
16. Peterson CM, Thomas DM, Blackburn GL, Heymsfield SB. The universal equation for estimating ideal body weight and body weight at any BMI. Am J Clin Nutr 2016;103:1197-203.
17. Cakmak B, Inanir A, Karakus N, Ates O, Yigit S. Association between the ACE gene I/D polymorphism and osteoporosis in a Turkish population. Z Rheumatol 2015;74:346-50.
18. Czerny B, Kaminski A, Kurzawski M, Kotrych D, Safranow K, Dziedziejko V, et al. The association of IL-1beta, IL-2, and IL-6 gene polymorphisms with bone mineral density and osteoporosis in postmenopausal women. Eur J Obstet Gynecol Reprod Biol 2010;149:82-5.
19. Oishi Y, Watanabe Y, Shinoda S, Naka M, Ozawa Y, Matsuyama T, et al. The IL6 gene polymorphism -634C>G and IL17F gene polymorphism 7488T>C influence bone mineral density in young and elderly Japanese women. Gene 2012;504:75-83.
20. Moura KF, Haidar M, Bonduki C, Feldner PC Jr, Silva I, Soares JM Jr, et al. Frequencies of interleukin-6, GST, and progesterone receptor gene polymorphisms in postmenopausal women with low bone mineral density. Sao Paulo Med J 2014;132:36-40.
21. Liu Z, Chen R, Jiang Y, Yang Y, He L, Luo C, et al. A meta-analysis of serum osteocalcin level in postmenopausal osteoporotic women compared to controls. BMC Musculoskelet Disord 2019;20:532.
22. Garcia-Martin A, Cortes-Berdonces M, Luque-Fernandez I, Rozas-Moreno P, Quesada-Charneco M, Munoz-Torres M. Osteocalcin as a marker of metabolic risk in healthy postmenopausal women. Menopause 2011;18:537-41.
23. Bhadricha H, Khatkhatay MI, Desai M. Development of an in-house ELISA for human intact osteocalcin and its utility in diagnosis and management of osteoporosis. Clin Chim Acta 2019;489:117-23.
24. Zhang XY, He JW, Fu WZ, Liu YJ, Zhang ZL. Associations of serum osteocalcin and polymorphisms of the osteocalcin gene with bone mineral density in postmenopausal and elderly Chinese women. J Nutrigenet Nutrigenomics 2016;9:231-42.
25. Bosnyak E, Trager E, Protzner A, Komka Z, Gyore I, Szmodis M, et al. Osteocalcin gene polymorphism and bone density in Hungarian athletes. Anthropol Anz 2016;73:2.
26. Ling Y, Gao X, Lin H, Ma H, Pan B, Gao J. A common polymorphism rs1800247 in the osteocalcin gene was associated with serum osteocalcin levels, bone mineral density, and fracture: the Shanghai Changfeng Study. Osteoporos Int 2016;27:769-79.