Association of Receptor Activator of Nuclear Factor kappa B Ligand (RANKL) (rs9533155, rs9533156) Gene Polymorphism with its Circulatory Level and Bone Mineral Density in Postmenopausal Women with and without Osteoporosis
Abstract
Introduction: The gene that codes for the receptor activator of nuclear factor kappa B ligand (RANKL) has been identified as a key regulator of osteoclastogenesis. It plays a key role in the remodeling of bones by affecting bone resorption. Objectives: The current study aims to evaluate the association pattern of single nucleotide polymorphism (SNP) of RANKL gene polymorphisms (rs9533155 (693C>G), rs9533156 (643T>C)) with its circulatory level and Bone Mineral Density (BMD) in North Indian postmenopausal women. Methods: In this study, 165 postmenopausal osteoporotic women were enrolled as patients (age 54.44 ± 6.00 years) and 165 postmenopausal non-osteoporotic women were enrolled as controls (age 54.47 ± 6.46 years). The BMD of all recruited subjects was determined, followed by genetic analysis by Polymerase Chain Reaction (PCR) and Restriction Fragment Length Polymorphism (RFLP) method. RANKL levels were also measured using Enzyme-Linked Immunosorbent Assay. Result: The current study demonstrated that the subjects with the GG genotype of rs9533155 have significantly decreased average BMD at the lumbar spine and forearm and increased RANKL serum levels as compared to homozygous wild-type CC and heterozygous CG genotypes. Furthermore, subjects with the homozygous wild TT genotype of rs9533156 showed significantly lower BMD at the femoral neck and higher RANKL serum level as compared to homozygous mutant CC and heterozygous TC genotypes. No significant difference was found in the frequency distribution of genotypes and alleles of rs9533155 and rs9533156 among osteoporotic patients and controls. Conclusion: Our results suggest that RANKL polymorphism may be linked to BMD variation and osteoporosis development in north Indian postmenopausal women.
Keywords:
BMD, Osteoporosis, Polymorphism, Postmenopausal Indian Women
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References
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González-Mercado, A., Sánchez-López, J., Perea-Díaz, F., Magaña-Torres, M., Salazar-Páramo, M., González-López, L., ... & Ibarra-Cortés, B. (2019). Association of polymorphisms of the TNFRSF11B and TNFSF11 genes with bone mineral density in postmenopausal women from western Mexico. Archives of Medical Science, 15(5), 1352-1356. https://doi.org/10.5114/aoms.2019.87410
Gravallese, E. M., Manning, C., Tsay, A., Naito, A., Pan, C., Amento, E., & Goldring, S. R. (2000). Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology, 43(2), 250-258. https://doi.org/10.1002/1529-0131(200002)43:2%3C250::aid-anr3%3E3.0.co;2-p
Haryono, I. R., Tulaar, A., Sudoyo, H., Purba, A., Abdullah, M., Jusman, S. W., ... & Ilyas, E. I. (2019). Polymorphisms within RANKL and Osteoprotegerin Genes in Low Bone Mass among Postmenopausal Indonesian Women. Türk Osteoporoz Dergisi, 25(1), 28-34. https://doi.org/10.4274/tod.galenos.2019.58815
Hofbauer, L. C. (1999). Osteoprotegerin ligand and osteoprotegerin: novel implications for osteoclast biology and bone metabolism. European Journal of Endocrinology, 141(3), 195-210. https://doi.org/10.1530/eje.0.1410195
Hofbauer, L. C., Khosla, S., Dunstan, C. R., Lacey, D. L., Boyle, W. J., & Riggs, B. L. (2000). The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. Journal of Bone and Mineral Research, 15(1), 2-12. https://doi.org/10.1359/jbmr.2000.15.1.2
Hsu, Y. H., Niu, T., Terwedow, H. A., Xu, X., Feng, Y., Li, Z., ... & Xu, X. (2006). Variation in genes involved in the RANKL/RANK/OPG bone remodeling pathway are associated with bone mineral density at different skeletal sites in men. Human Genetics, 118, 568-577. https://doi.org/10.1007/s00439-005-0062-4
Jones, D. H., Kong, Y. Y., & Penninger, J. M. (2002). Role of RANKL and RANK in bone loss and arthritis. Annals of the rheumatic diseases, 61(suppl 2), ii32-ii39. https://doi.org/10.1136/ard.61.suppl_2.ii32
Kanis, J. A., Melton, L. J., Christiansen, C., Johnston, C. C., & Khaltaev, N. (1994). The diagnosis of osteoporosis. Journal of Bone and Mineral Research, 9(8), 1137-1141. https://doi.org/10.1002/jbmr.5650090802
Kanis, J. A., Oden, A., McCloskey, E. V., Johansson, H., Wahl, D. A., Cooper, C., & IOF Working Group on Epidemiology and Quality of Life. (2012). A systematic review of hip fracture incidence and probability of fracture worldwide. Osteoporosis International, 23, 2239-2256. https://doi.org/10.1007/s00198-012-1964-3
Khadilkar, A. V., & Mandlik, R. M. (2015). Epidemiology and treatment of osteoporosis in women: an Indian perspective. International Journal of Women's Health, 841-850. https://doi.org/10.2147/IJWH.S54623
Kong, Y. Y., Feige, U., Sarosi, I., Bolon, B., Tafuri, A., Morony, S., ... & Penninger, J. M. (1999). Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature, 402(6759), 304-309. https://doi.org/10.1016/s0092-8674(00)81569-x
Lacey, D. L., Timms, E., Tan, H. L., Kelley, M. J., Dunstan, C. R., Burgess, T., ... & Boyle, W. J. (1998). Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell, 93(2), 165-176. https://doi.org/10.1016/s0092-8674(00)81569-x
Liu, J. M., Zhang, M. J., Zhao, L., Cui, B., Li, Z. B., Zhao, H. Y., ... & Ning, G. (2010). Analysis of recently identified osteoporosis susceptibility genes in Han Chinese women. The Journal of Clinical Endocrinology & Metabolism, 95(9), E112-E120. https://doi.org/10.1210/jc.2009-2768
Malhotra, N., & Mithal, A. (2008). Osteoporosis in Indians. Indian Journal of Medical Research, 127(3), 263-268. Available at: https://journals.lww.com/ijmr/abstract/2008/27030/osteoporosis_in_indians.9.aspx
Manolagas, S. C. (2000). Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocrine Reviews, 21(2), 115-137. https://doi.org/10.1210/edrv.21.2.0395
Mencej, S., Albagha, O. M., Prezelj, J., Kocjan, T., & Marc, J. (2008). Tumour necrosis factor superfamily member 11 gene promoter polymorphisms modulate promoter activity and influence bone mineral density in postmenopausal women with osteoporosis. Journal of Molecular Endocrinology, 40(6), 273-280. https://doi.org/10.1677/jme-08-0003
Mencej, S., Preželj, J., Kocijančič, A., Ostanek, B., & Marc, J. (2006). Association of TNFSF11 gene promoter polymorphisms with bone mineral density in postmenopausal women. Maturitas, 55(3), 219-226. https://doi.org/10.1016/j.maturitas.2006.03.004
Nabipour, I., Larijani, B., Vahdat, K., Assadi, M., Jafari, S. M., Ahmadi, E., ... & Amiri, Z. (2009). Relationships among serum receptor of nuclear factor-κB ligand, osteoprotegerin, high-sensitivity C-reactive protein, and bone mineraldensity in postmenopausal women: Osteoimmunity versus osteoinflammatory. Menopause, 16(5), 950-955. https://doi.org/10.1097/gme.0b013e3181a181b8
Nakashima, T., Hayashi, M., & Takayanagi, H. (2012). New insights into osteoclastogenic signaling mechanisms. Trends in Endocrinology & Metabolism, 23(11), 582-590. https://doi.org/10.1016/j.tem.2012.05.005
Nguyen, T. V., Blangero, J., & Eisman, J. A. (2000). Genetic epidemiological approaches to the search for osteoporosis genes. Journal of Bone and Mineral Research, 15(3), 392-401. https://doi.org/10.1359/jbmr.2000.15.3.392
Oelzner, P., Franke, S., Lehmann, G., Eidner, T., Müller, A., Wolf, G., & Hein, G. (2007). Soluble receptor activator of NFkappa B-ligand and osteoprotegerin in rheumatoid arthritis-relationship with bone mineral density, disease activity and bone turnover. Clinical Rheumatology, 26, 2127-2135. https://doi.org/10.1007/s10067-007-0639-5
Okamoto, K., Nakashima, T., Shinohara, M., Negishi-Koga, T., Komatsu, N., Terashima, A., ... & Takayanagi, H. (2017). Osteoimmunology: the conceptual framework unifying the immune and skeletal systems. Physiological Reviews, 97(4), 1295-1349. https://doi.org/10.1152/physrev.00036.2016
Pocock, N. A., Eisman, J. A., Hopper, J. L., Yeates, M. G., Sambrook, P. N., & Eberl, S. (1987). Genetic determinants of bone mass in adults. A twin study. The Journal of Clinical Investigation, 80(3), 706-710. https://doi.org/10.1172/jci113125
Ralston, S. H., & de Crombrugghe, B. (2006). Genetic regulation of bone mass and susceptibility to osteoporosis. Genes & development, 20(18), 2492-2506. https://doi.org/10.1101/gad.1449506
Saidenberg-Kermanac'h, N., Corrado, A., Lemeiter, D., Devernejoul, M. C., Boissier, M. C., & Cohen-Solal, M. E. (2004). TNF-α antibodies and osteoprotegerin decrease systemic bone loss associated with inflammation through distinct mechanisms in collagen-induced arthritis. Bone, 35(5), 1200-1207. https://doi.org/10.1016/j.bone.2004.07.004
Sassi, R., Sahli, H., Cheour, E., Sellami, S., & El Gaaied, A. B. A. (2017). -643C > T RANKL gene polymorphism is associated with osteoporosis in Tunisian postmenopausal women. Climacteric, 20(4), 374-378. https://doi.org/10.1080/13697137.2017.1315088
Seeman, E., Bianchi, G., Khosla, S., Kanis, J. A., & Orwoll, E. (2006). Bone fragility in men-where are we?. Osteoporosis International, 17, 1577-1583. https://doi.org/10.1007/s00198-006-0160-8
Shang, M., Lin, L., & Cui, H. (2013). Association of genetic polymorphisms of RANK, RANKL and OPG with bone mineral density in Chinese peri-and postmenopausal women. Clinical biochemistry, 46(15), 1493-1501. https://doi.org/10.3390/genes12020200
Stern, A., Laughlin, G. A., Bergstrom, J., & Barrett-Connor, E. (2007). The sex-specific association of serum osteoprotegerin and receptor activator of nuclear factor κB legend with bone mineral density in older adults: the Rancho Bernardo study. European Journal of Endocrinology, 156(5), 555-562. https://doi.org/10.1530/EJE-06-0753
Styrkarsdottir, U., Halldorsson, B. V., Gretarsdottir, S., Gudbjartsson, D. F., Walters, G. B., Ingvarsson, T., ... & Stefansson, K. (2008). Multiple genetic loci for bone mineral density and fractures. New England Journal of Medicine, 358(22), 2355-2365. https://doi.org/10.1056/nejmoa0801197
Styrkarsdottir, U., Halldorsson, B. V., Gretarsdottir, S., Gudbjartsson, D. F., Walters, G. B., Ingvarsson, T., ... & Stefansson, K. (2009). New sequence variants associated with bone mineral density. Nature genetics, 41(1), 15-17. https://doi.org/10.1038/ng.284
Takács, I., Lazáry, Á., Kósa, J. P., Kiss, J., Balla, B., Nagy, Z., ... & Lakatos, P. (2010). Allelic variations of RANKL/OPG signaling system are related to bone mineral density and in vivo gene expression. European Journal of Endocrinology, 162(2), 423-431. http://dx.doi.org/10.1530/EJE-09-0617
Teitelbaum, S. L. (2004). Postmenopausal osteoporosis, T cells, and immune dysfunction. Proceedings of the National Academy of Sciences, 101(48), 16711-16712. https://doi.org/10.1073/pnas.0407335101
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Dixit, P., Ahmad, I., Waliullah, S., & Jafar, T. (2025). Association of Receptor Activator of Nuclear Factor kappa B Ligand (RANKL) (rs9533155, rs9533156) Gene Polymorphism with its Circulatory Level and Bone Mineral Density in Postmenopausal Women with and without Osteoporosis. International Journal of Advancement in Life Sciences Research, 8(2), 1-12. https://doi.org/https://doi.org/10.31632/ijalsr.2025.v08i02.001
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