Genetic variants in the retinoid X receptor gene contribute to osteoarthritis susceptibility

Authors

  • Debora Štefik Institute for Medical Research, Military Medical Academy, Crnotravska 17, 11000 Belgrade, Serbia https://orcid.org/0000-0001-6610-4812
  • Vladimir Vranić Clinic for Orthopedic Surgery and Traumatology, Military Medical Academy, Crnotravska 17, 11000 Belgrade, Serbia
  • Nemanja Ivković Institute for Medical Research, Military Medical Academy, Crnotravska 17, 11000 Belgrade, Serbia https://orcid.org/0000-0001-8982-8848
  • Biljana Božić Nedeljković Faculty of Biology, University of Belgrade, Studentski trg 3, 11000 Belgrade, Serbia https://orcid.org/0000-0002-1238-1731
  • Gordana Šupić 1. Institute for Medical Research, Military Medical Academy, Crnotravska 17, 11000 Belgrade, Serbia; 2. Medical Faculty of Military Medical Academy, University of Defense, 11000 Belgrade, Serbia https://orcid.org/0000-0003-0350-4733

DOI:

https://doi.org/10.2298/ABS240306010S

Keywords:

retinoid X receptor (RXR), polymorphism, osteoarthritis, inflammation

Abstract

Paper description:

  • Osteoarthritis, a progressive joint disease characterized by persistent inflammation, has both hereditary and environmental causes.
  • This study is the first to examine the association between osteoarthritis and polymorphisms in the RXRα gene, which regulates inflammatory pathways and acts as a transcriptional partner of vitamin D3 and retinoic acid receptors.
  • The RXRα polymorphism rs7864987 is associated with an increased risk of osteoarthritis (P=0.012), while rs3118523 reduces its risk (P=0.030).
  • RXRα is an inflammation-related gene involved in the complex network underlying the immunopathology of osteoarthritis, and its polymorphisms could potentially drive individualized retinoid therapy for osteoarthritis.

Abstract: Osteoarthritis (OA) is a progressive disease of the joints that causes a gradual loss of function, resulting in limited mobility. Chronic inflammation is the main molecular process that triggers and propagates this disease. The retinoid X receptor (RXR), a member of the nuclear receptor family, is involved in modulating inflammatory pathways by influencing key pro-catabolic inflammatory cytokines, chemokines, and enzymes responsible for instigating and sustaining chronic joint inflammation. We evaluated the association between OA risk and genetic variants in the RXRα isoform. Compared to control individuals, a statistically significant difference in genotype distribution was detected for the rs7864987 polymorphism (P=0.008), while a positive inclination toward association was noted for rs3118523 (P=0.077). According to our findings based on the additive model, it appears that RXRα rs7864987 is linked to a higher risk of OA (adjusted odds ratio (OR)=1.846, P=0.012), whereas rs3118523 is associated with decreased risk of OA (adjusted OR=0.569, P=0.030). These results suggest that RXRα could be a significant inflammation-related gene involved in the complex network underlying the immunopathology of osteoarthritis. RXRα polymorphisms could potentially drive individualized retinoid therapy for OA based on genetic profile.

Downloads

Download data is not yet available.

References

Roseti L, Desando G, Cavallo C, Petretta M, Grigolo B. Articular Cartilage Regeneration in Osteoarthritis. Cells. 2019;8(11):1305. https://doi.org/10.3390/cells8111305

Stefik D, Vranic V, Ivkovic N, Velikic G, Maric DM, Abazovic D, Vojvodic D, Maric DL, Supic G. Potential Impact of Polymorphisms in Toll-like Receptors 2, 3, 4, 7, 9, miR-146a, miR-155, and miR-196a Genes on Osteoarthritis Susceptibility. Biology. 2023;12(3):458. https://doi.org/10.3390/biology12030458

van den Bosch MHJ. Inflammation in osteoarthritis: is it time to dampen the alarm(in) in this debilitating disease? Clin Exp Immunol. 2019;195(2):153-66. https://doi.org/10.1111/cei.13237

Chow YY, Chin KY. The Role of Inflammation in the Pathogenesis of Osteoarthritis. Mediators Inflamm. 2020;2020:1-19. https://doi.org/10.1155/2020/8293921

le Maire, Teyssier, Balaguer, Bourguet, Germain. Regulation of RXR-RAR Heterodimers by RXR- and RAR-Specific Ligands and Their Combinations. Cells. 2019;8(11):1392. https://doi.org/10.3390/cells8111392

García P, Lorenzo P, de Lera AR. Natural ligands of RXR receptors. In: Pahl E, editor. Retinoid Signaling Pathways. . Elsevier; 2020;637:209-34. (Methods in Enzymology; Vol. 637)https://doi.org/10.1016/bs.mie.2020.02.006

Krężel W, Rühl R, de Lera AR. Alternative retinoid X receptor (RXR) ligands. Mol Cell Endocrinol. 2019;491:110436. https://doi.org/10.1016/j.mce.2019.04.016

Li B, Cai SY, Boyer JL. The role of the retinoid receptor, RAR/RXR heterodimer, in liver physiology. Biochim Biophys Acta BBA - Mol Basis Dis. 2021;1867(5):166085. https://doi.org/10.1016/j.bbadis.2021.166085

Evans RM, Mangelsdorf DJ. Nuclear Receptors, RXR & the Big Bang. Cell. 2014;157(1):255–66. https://doi.org/10.1016/j.cell.2014.03.012

Hanish BJ, Hackney Price JF, Kaneko I, Ma N, van der Vaart A, Wagner CE, Jurutka PW, Marshall PA. A novel gene expression analytics-based approach to structure aided design of rexinoids for development as next-generation cancer therapeutics. Steroids. 2018;135:36-49. https://doi.org/10.1016/j.steroids.2018.04.009

Haussler MR, Whitfield GK, Kaneko I, Haussler CA, Hsieh D, Hsieh JC, Jurutka PW. Molecular Mechanisms of Vitamin D Action. Calcif Tissue Int. 2013;92(2):77-98. https://doi.org/10.1007/s00223-012-9619-0

Lv J, Feng L, Bao Z, Guo H, Zhang Y, Jiao W, Zhang L, Wang S, He Y, Hu X. Molecular Characterization of RXR (Retinoid X Receptor) Gene Isoforms from the Bivalve Species Chlamys farreri. PLoS ONE. 2013;8(9):e74290. https://doi.org/10.1371/journal.pone.0074290

Almeida NR, Conda‐Sheridan M. A review of the molecular design and biological activities of RXR agonists. Med Res Rev. 2019;39(4):1372-97. https://doi.org/10.1002/med.21578

Núñez V, Alameda D, Rico D, Mota R, Gonzalo P, Cedenilla M, Fischer T, Boscá L, Glass CK, Arroyo AG, Ricote M. Retinoid X receptor α controls innate inflammatory responses through the up-regulation of chemokine expression. Proc Natl Acad Sci U S A. 2010;107(23):10626-31. https://doi.org/10.1073/pnas.0913545107

Rőszer T, Menéndez-Gutiérrez MP, Lefterova MI, Alameda D, Núñez V, Lazar MA, Fischer T, Ricote M. Autoimmune Kidney Disease and Impaired Engulfment of Apoptotic Cells in Mice with Macrophage Peroxisome Proliferator-Activated Receptor γ or Retinoid X Receptor α Deficiency. J Immunol Baltim Md 1950. 2011;186(1):621-31. https://doi.org/10.4049/jimmunol.1002230

Pan J, Guleria RS, Zhu S, Baker KM. Molecular Mechanisms of Retinoid Receptors in Diabetes-Induced Cardiac Remodeling. J Clin Med. 2014;3(2):566-94. https://doi.org/10.3390/jcm3020566

Sharma S, Shen T, Chitranshi N, Gupta V, Basavarajappa D, Sarkar S, Mirzaei M, You Y, Krezel W, Graham SL, Gupta V. Retinoid X Receptor: Cellular and Biochemical Roles of Nuclear Receptor with a Focus on Neuropathological Involvement. Mol Neurobiol. 2022;59(4):2027-50. https://doi.org/10.1007/s12035-021-02709-y

Pande M, Thompson PA, Do KA, Sahin AA, Amos CI, Frazier ML, Bondy ML, Brewster AM. Genetic variants in the vitamin D pathway and breast cancer disease-free survival. Carcinogenesis. 2013;34(3):587-94. https://doi.org/10.1093/carcin/bgs369

Jacobs ET, Martínez ME, Campbell PT, Conti DV, Duggan D, Figueiredo JC, Haile RW, LeRoy EC, Poynter JN, Thompson PA, Baron JA. Genetic variation in the retinoid X receptor and calcium-sensing receptor and risk of colorectal cancer in the Colon Cancer Family Registry. Carcinogenesis. 2010;31(8):1412-6. https://doi.org/10.1093/carcin/bgq127

Mostowska A, Sajdak S, Pawlik P, Lianeri M, Jagodzinski PP. Polymorphic variants in the vitamin D pathway genes and the risk of ovarian cancer among non-carriers of BRCA1/BRCA2 mutations. Oncol Lett. 2016;11(2):1181-8. https://doi.org/10.3892/ol.2015.4033

Kerkhof HJM, Lories RJ, Meulenbelt I, Jonsdottir I, Valdes AM, Arp P, Ingvarsson T, Jhamai M, Jonsson H, Stolk L, Thorleifsson G, Zhai G, Zhang F, Zhu Y, Van Der Breggen R, Carr A, Doherty M, Doherty S, Felson DT, Gonzalez A, Halldorsson BV, Hart DJ, Hauksson VB, Hofman A, Ioannidis JPA, Kloppenburg M, Lane NE, Loughlin J, Luyten FP, Nevitt MC, Parimi N, Pols HAP, Rivadeneira F, Slagboom EP, Styrkársdóttir U, Tsezou A, Van De Putte T, Zmuda J, Spector TD, Stefansson K, Uitterlinden AG, Van Meurs JBJ. A genome‐wide association study identifies an osteoarthritis susceptibility locus on chromosome 7q22. Arthritis Rheum. 2010;62(2):499-510. https://doi.org/10.1002/art.27184

Nakajima M, Takahashi A, Kou I, Rodriguez-Fontenla C, Gomez-Reino JJ, Furuichi T, Dai J, Sudo A, Uchida A, Fukui N, Kubo M, Kamatani N, Tsunoda T, Malizos KN, Tsezou A, Gonzalez A, Nakamura Y, Ikegawa S. New Sequence Variants in HLA Class II/III Region Associated with Susceptibility to Knee Osteoarthritis Identified by Genome-Wide Association Study. Agarwal S, editor. PLoS ONE. 2010;5(3):e9723. https://doi.org/10.1371/journal.pone.0009723

Cornelis FMF, Luyten FP, Lories RJ. Functional effects of susceptibility genes in osteoarthritis. Discov Med. 2011;12(63):129-39.

Loughlin J. Genetic epidemiology of primary osteoarthritis: Curr Opin Rheumatol. 2001;13(2):111-6. https://doi.org/10.1097/00002281-200103000-00004

Ward LD, Kellis M. HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease. Nucleic Acids Res. 2016;44(D1):D877-881. https://doi.org/10.1093/nar/gkv1340

Leal AS, Reich LA, Moerland JA, Zhang D, Liby KT. Potential therapeutic uses of rexinoids. In: Copple BL, Rockwell CE, editors. Advances in Immunopharmacology. Elsevier; 2021;91:141–83. (Advances in Pharmacology ; Vol. 91)https://doi.org/10.1016/bs.apha.2021.01.004

Germain P, Chambon P, Eichele G, Evans RM, Lazar MA, Leid M, De Lera AR, Lotan R, Mangelsdorf DJ, Gronemeyer H. International Union of Pharmacology. LXIII. Retinoid X Receptors. Pharmacol Rev. 2006;58(4):760-72. https://doi.org/10.1124/pr.58.4.7

Cooper DN. Functional intronic polymorphisms: Buried treasure awaiting discovery within our genes. Hum Genomics. 2010;4(5):284-8. https://doi.org/10.1186/1479-7364-4-5-284

Bittner N, Shi C, Zhao D, Ding J, Southam L, Swift D, Kreitmaier P, Tutino M, Stergiou O, Cheung JTS, Katsoula G, Hankinson J, Wilkinson JM, Orozco G, Zeggini E . Primary osteoarthritis chondrocyte map of chromatin conformation reveals novel candidate effector genes. Ann Rheum Dis. 2024;ard-2023-224945. https://doi.org/10.1136/ard-2023-224945

Lee JJ, Wu X, Hildebrandt MAT, Yang H, Khuri FR, Kim E, Gu J, Ye Y, Lotan R, Spitz MR, Hong WK. Global Assessment of Genetic Variation Influencing Response to Retinoid Chemoprevention in Head and Neck Cancer Patients. Cancer Prev Res (Phila Pa). 2011;4(2):185-93. https://doi.org/10.1158/1940-6207.CAPR-10-0125

Karami S, Brennan P, Rosenberg PS, Navratilova M, Mates D, Zaridze D, Janout V, Kollarova H, Bencko V, Matveev V, Szeszenia-Dabrowska N, Holcatova I, Yeager M, Chanock S, Menashe I, Rothman N, Chow WH, Boffetta P, Moore LE. Analysis of SNPs and Haplotypes in Vitamin D Pathway Genes and Renal Cancer Risk. PLoS ONE. 2009;4(9). https://doi.org/10.1371/journal.pone.0007013

McKinney BA, Lareau C, Oberg AL, Kennedy RB, Ovsyannikova IG, Poland GA. The Integration of Epistasis Network and Functional Interactions in a GWAS Implicates RXR Pathway Genes in the Immune Response to Smallpox Vaccine. PloS One. 2016;11(8):e0158016. https://doi.org/10.1371/journal.pone.0158016

Zhang R, Fu Z, Fan H, Tian T, Wu M, Xie C, Huang P, Yu R, Zhang Y, Zhang W, Wang J. Genetic variant of RXR involved in the vitamin D metabolic pathway was linked to HCV infection outcomes among a high-risk Chinese population. Infect Genet Evol J Mol Epidemiol Evol Genet Infect Dis. 2021;87:104641. https://doi.org/10.1016/j.meegid.2020.104641

Zhu L, Kamalathevan P, Koneva LA, Zarebska JM, Chanalaris A, Ismail H, Wiberg A, Ng M, Muhammad H, Walsby-Tickle J, McCullagh JSO, Watt FE, Oxford Hand Surgical Team, Sansom SN, Furniss D, Gardiner MD, Vincent TL, Riley N, Spiteri M, McNab I, Little C, Cogswell L, Critchley P, Giele H, Shirley R. Variants in ALDH1A2 reveal an anti-inflammatory role for retinoic acid and a new class of disease-modifying drugs in osteoarthritis. Sci Transl Med. 2022;14(676):eabm4054. https://doi.org/10.1126/scitranslmed.abm4054

Chow EKH, Razani B, Cheng G. Innate immune system regulation of nuclear hormone receptors in metabolic diseases. J Leukoc Biol. 2007;82(2):187-95. https://doi.org/10.1189/jlb.1206741.

Wang Y, Moser AH, Shigenaga JK, Grunfeld C, Feingold KR. Downregulation of liver X receptor-α in mouse kidney and HK-2 proximal tubular cells by LPS and cytokines. J Lipid Res. 2005;46(11):2377–87. https://doi.org/10.1194/jlr.M500134-JLR200

Tong X, Zeng H, Gu P, Wang K, Zhang H, Lin X. Monocyte chemoattractant protein‑1 promotes the proliferation, migration and differentiation potential of fibroblast‑like synoviocytes via the PI3K/P38 cellular signaling pathway. Mol Med Rep. 2020;21(3):1623-32. https://doi.org/10.3892/mmr.2020.10969

Collins-Racie LA, Yang Z, Arai M, Li N, Majumdar MK, Nagpal S, Mounts WM, Dorner AJ, Morris E, LaVallie ER. Global analysis of nuclear receptor expression and dysregulation in human osteoarthritic articular cartilage. Osteoarthritis Cartilage. 2009;17(7):832-42. https://doi.org/10.1016/j.joca.2008.12.011

Li Y, Xing Q, Wei Y, Zhao L, Zhang P, Han X, Wang J. Activation of RXR by bexarotene inhibits inflammatory conditions in human rheumatoid arthritis fibroblast‑like synoviocytes. Int J Mol Med. 2019;44(5):1963-70. https://doi.org/10.3892/ijmm.2019.4336

Wojdasiewicz P, Poniatowski ŁA, Szukiewicz D. The Role of Inflammatory and Anti-Inflammatory Cytokines in the Pathogenesis of Osteoarthritis. Mediators Inflamm. 2014;2014:561459. https://doi.org/10.1155/2014/561459

Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol. 2011;7(1):33-42. https://doi.org/10.1038/nrrheum.2010.196

Brinckerhoff CE, Coffey JW, Sullivan AC. Inflammation and Collagenase Production in Rats with Adjuvant Arthritis Reduced with 13- cis -Retinoic Acid. Science. 1983;221(4612):756-8. https://doi.org/10.1126/science.6308759.

Kirchmeyer M, Koufany M, Sebillaud S, Netter P, Jouzeau JY, Bianchi A. All-trans retinoic acid suppresses interleukin-6 expression in interleukin-1-stimulated synovial fibroblasts by inhibition of ERK1/2pathway independently of RAR activation. Arthritis Res Ther. 2008;10(6):R141. https://doi.org/10.1186/ar2569

Campbell FC, Xu H, El-Tanani M, Crowe P, Bingham V. The Yin and Yang of vitamin D receptor (VDR) signaling in neoplastic progression: Operational networks and tissue-specific growth control. Biochem Pharmacol. 2010;79(1):1. https://doi.org/10.1016/j.bcp.2009.09.005

Joseph SB, Castrillo A, Laffitte BA, Mangelsdorf DJ, Tontonoz P. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat Med. 2003;9(2):213-9. https://doi.org/10.1038/nm820

Chute JP, Ross JR, McDonnell DP. Minireview: Nuclear Receptors, Hematopoiesis, and Stem Cells. Mol Endocrinol. 2010;24(1):1-10. https://doi.org/10.1210/me.2009-0332

Ma X, Warnier M, Raynard C, Ferrand M, Kirsh O, Defossez PA, Martin N, Bernard D. The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling. Aging Cell. 2018;17(6):e12831. https://doi.org/10.1111/acel.12831

Shen D, Yu X, Wu Y, Chen Y, Li G, Cheng F, Xia L. Emerging roles of bexarotene in the prevention, treatment and anti-drug resistance of cancers. Expert Rev Anticancer Ther. 2018;18(5):487-99. https://doi.org/10.1080/14737140.2018.1449648

Bomben V, Holth J, Reed J, Cramer P, Landreth G, Noebels J. Bexarotene reduces network excitability in models of Alzheimer’s disease and epilepsy. Neurobiol Aging. 2014;35(9):2091-5. https://doi.org/10.1016/j.neurobiolaging.2014.03.029

McFarland K, Spalding TA, Hubbard D, Ma JN, Olsson R, Burstein ES. Low Dose Bexarotene Treatment Rescues Dopamine Neurons and Restores Behavioral Function in Models of Parkinson’s Disease. ACS Chem Neurosci. 2013;4(11):1430-8. https://doi.org/10.1021/cn400100f.

Riancho J, Ruiz-Soto M, Berciano MT, Berciano J, Lafarga M. Neuroprotective Effect of Bexarotene in the SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis. Front Cell Neurosci. 2015;9:250. https://doi.org/10.3389/fncel.2015.00250

Natrajan MS, de la Fuente AG, Crawford AH, Linehan E, Nuñez V, Johnson KR, Wu T, Fitzgerald DC, Ricote M, Bielekova B, Franklin RJM. Retinoid X receptor activation reverses age-related deficiencies in myelin debris phagocytosis and remyelination. Brain. 2015;138(12):3581-97. https://doi.org/10.1093/brain/awv289

Certo M, Endo Y, Ohta K, Sakurada S, Bagetta G, Amantea D. Activation of RXR/PPARγ underlies neuroprotection by bexarotene in ischemic stroke. Pharmacol Res. 2015;102:298-307. https://doi.org/10.1016/j.phrs.2015.10.009

Kamalathevan P, Zhu L, Muhammad H, Furniss D, Vincent T. MAINTAINING ALL-TRANS RETINOIC ACID LEVELS WITH TALAROZOLE SUPPRESSES MECHANFLAMMATION FOLLOWING CARTILAGE INJURY THROUGH A PERIXOSOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA-DEPENDENT MECHANISM. Osteoarthritis Cartilage. 2022;30:S181. https://doi.org/10.1016/j.joca.2022.02.240

Zha Z, Han Q, Huo S. The protective effects of bexarotene against advanced glycation end-product (AGE)-induced degradation of articular extracellular matrix (ECM). Artif Cells Nanomedicine Biotechnol. 2020;48(1):1-7. https://doi.org/10.1080/21691401.2019.1699802

Li H, Li X, Yang B, Su J, Cai S, Huang J, Hu T, Chen L, Xu Y, Li Y. The retinoid X receptor α modulator K-80003 suppresses inflammatory and catabolic responses in a rat model of osteoarthritis. Sci Rep. 2021;11(1):16956. https://doi.org/10.1038/s41598-021-96517-y

Madry H, Kon E, Condello V, Peretti GM, Steinwachs M, Seil R, Berruto M, Engebretsen L, Filardo G, Angele P. Early osteoarthritis of the knee. Knee Surg Sports Traumatol Arthrosc Off J ESSKA. 2016;24(6):1753-62. https://doi.org/10.1007/s00167-016-4068-3.

van Berkel AC, Schiphof D, Waarsing JH, Runhaar J, van Ochten JM, Bindels PJE, Bierma-Zeinstra SMA. 10-Year natural course of early hip osteoarthritis in middle-aged persons with hip pain: a CHECK study. Ann Rheum Dis. 2021;80(4):487-93. https://doi.org/10.1136/annrheumdis-2020-218625

Downloads

Published

2024-07-10

How to Cite

1.
Štefik D, Vranić V, Ivković N, Božić Nedeljković B, Šupić G. Genetic variants in the retinoid X receptor gene contribute to osteoarthritis susceptibility . Arch Biol Sci [Internet]. 2024Jul.10 [cited 2024Nov.25];76(2):151-60. Available from: https://serbiosoc.org.rs/arch/index.php/abs/article/view/9618

Issue

Vol. 76 No. 2 (2024)

Section

Articles

License

Copyright (c) 2024 Debora Štefik, Vladimir Vranić, Nemanja Ivković, Biljana Božić Nedeljković, Gordana Šupić

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Authors grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution 4.0 International License that allows others to share the work with an acknowledgment of the work’s authorship and initial publication in this journal.

Most read articles by the same author(s)