Molecular Biology Reports

, Volume 45, Issue 5, pp 1089–1098 | Cite as

Gene–gene interactions of the Wnt/β-catenin signaling pathway in knee osteoarthritis

  • Javier Fernández-Torres
  • Yessica Zamudio-Cuevas
  • Alberto López-Reyes
  • Daniela Garrido-Rodríguez
  • Karina Martínez-Flores
  • Carlos Alberto Lozada
  • José Francisco Muñóz-Valle
  • Edith Oregon-Romero
  • Gabriela Angélica Martínez-NavaEmail author
Original Article


This study was designed to investigate whether genetic polymorphisms of the Wnt/β-catenin signaling pathway and its interactions are involved in the development of knee osteoarthritis (KOA). Patients with KOA (n = 131) and healthy individuals (n = 190) with different ancestry from two Mexican populations (Mexico City and Guadalajara City) were analyzed. Twenty-five SNPs from thirteen genes (WISP1, DKK1, SOST, FRZB, LRP1, LRP4, LRP5, LRP6, GSKB, ADAMTS5, GDF5, FMN2 and COL11A1) involved in the Wnt/β-catenin signaling pathway were genotyped. Genetic and allelic frequencies and gene–gene interactions were performed for this study. After adjusting for age, sex, BMI and admixture, significant associations were found for five SNPs in Mexico City: LRP6 rs12314259 (G/G genotype OR 0.22, P = 0.029; and G allele OR 0.48, P = 0.022), SOST rs851054 (C/T genotype OR 0.42, P = 0.027; and T allele OR 0.62, P = 0.026), FMN2 rs986690 (G/A genotype OR 0.42, P = 0.034; and A allele OR 0.50, P = 0.015), FRZB rs409238 (A/G genotype, OR 2.41, P = 0.022), and COL11A1 rs2615977 (A/C genotype OR 2.39, P = 0.024); no associations for Guadalajara City were found. With respect to gene–gene interactions, the pairwise interactions of WISP1–COL11A1, COL11A1–FRZB, FRZB–SOST and WISP1–FMN2 make it possible to visualize the synergistic or antagonistic effect of their genotypes or alleles in both populations. These results suggest that gene–gene interactions in the Wnt/β-catenin signaling pathway play a role in the etiology of KOA.


Gene–gene interactions Wnt/β-catenin signaling pathway Osteoarthritis SNPs 



The study was funded by departmental resources.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Supplementary material

11033_2018_4260_MOESM1_ESM.tiff (128 kb)
Supplementary Fig. 1. Inferred genetic ancestry of P1 and P2 subjects. A) STRUCTURE bar plot for k = 3 including the data of putative parental African (AFR), European (EUR) and Amerindian (AMR) populations. Each bar represents the genetic data from one individual, and the colors correspond to inferred ancestral population (AFR in green, EUR in blue and AMR in red). B) Structure ternary plot for P1 (orange) and P2 (yellow) subjects anchored by the three putative parental population (AFR in green, EUR in blue and AMR in red)—Supplementary material 1 (TIFF 127 KB)


  1. 1.
    Wang CJ, Cheng JH, Chou WY, Hsu SL, Chen JH, Huang CY (2017) Changes of articular cartilage and subchondral bone after extracorporeal shockwave therapy inosteoarthritis of the knee. Int J Med Sci 14:213–223CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Kraus VB, Blanco FJ, Englund M, Karsdal MA, Lohmander LS (2015) Call for standardized definitions of osteoarthritis and risk stratification for clinical trials and clinical use. Osteoarthr Cartil 23:1233–1241CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Arden N, Nevitt M (2006) Osteoarthritis: epidemiology. Best Pract Res Clin Rheumatol 20:3–25CrossRefPubMedGoogle Scholar
  4. 4.
    De Filippis L, Gulli S, Caliri A, Romano C, Munaó F, Trimarchi G et al (2004) Epidemiology and risk factors in osteoarthritis: literature review data from “OASIS” study. Reumatismo 56:169–184PubMedGoogle Scholar
  5. 5.
    Woolf AD, Pfleger B (2003) Burden of major musculoskeletal conditions. Bull World Health Organ 81:646–656PubMedPubMedCentralGoogle Scholar
  6. 6.
    Peláez-Ballestas I, Sanin LH, Moreno-Montoya J, Alvarez-Nemegyei J, Burgos-Vargas R, Garza-Elizondo M et al (2011) Epidemiology of the rheumatic diseases in Mexico. A study of 5 regions based on the COPCORD Methodology. J Rheumatol Suppl 86:3–8CrossRefPubMedGoogle Scholar
  7. 7.
    Saito-Diaz K, Chen TW, Wang X, Thorne CA, Wallace HA, Page-McCaw A, Lee E (2013) The way Wnt works: components and mechanism. Growth Factors 31:1–31CrossRefPubMedGoogle Scholar
  8. 8.
    Blom A, Brockbank S, Lent P, Beuningen H, Geurts J, Takahashi N, Kraan P, Loo F, Schreurs W, Clements K, Newham P, Berg W (2009) Involvement of the Wnt signaling pathway in experimental and human osteoarthritis. Arthritis Rheum 60:501–512CrossRefPubMedGoogle Scholar
  9. 9.
    Gonzalez A (2013) Osteoarthritis year 2013 in review: genetics and genomics. Osteoarthr Cartil 21:1443–1451CrossRefPubMedGoogle Scholar
  10. 10.
    Loeser RF (2013) Osteoarthritis year in review 2013: biology. Osteoarthr Cartil 21:1436–1442CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Ono M, Inkson C, Kilts T, Young M (2011) WISP-1/CCN4 regulates by enhancing BMP-2 activity. J Bone Miner Res 26:193–208CrossRefPubMedGoogle Scholar
  12. 12.
    Kumarasinghe DD, Hopwood B, Kuliwaba JS, Atkins GJ, Fazzalari NL (2011) An update on primary hip osteoarthritis including altered Wnt and TGF-β associated gene expression from the bony component of the disease. Rheumatology 50:2166–2175CrossRefPubMedGoogle Scholar
  13. 13.
    Chun JS, Oh H, Yang S, Park M (2008) Wnt signaling in cartilage development and degeneration. BMB Rep 41:485–494CrossRefPubMedGoogle Scholar
  14. 14.
    Brigstock DR (2003) The CCN family: a new stimulus package. J Endocrinol 178:169–175CrossRefPubMedGoogle Scholar
  15. 15.
    Ochoa-Hernández AB, Juárez-Vázquez CI, Rosales-Reynoso MA, Barros-Núñez P (2012) WNT-β-catenin signaling pathway and its relationship with cancer. Cir Cir 80:389–398PubMedGoogle Scholar
  16. 16.
    Staines KA, Macrae VE, Farguharson C (2012) Cartilage development and degeneration: a Wnt situation. Cell Biochem Funct 30:633–642CrossRefPubMedGoogle Scholar
  17. 17.
    Schett G, Zwerina J, David JP (2008) The role of Wnt proteins in arthritis. Nat Clin Pract Rheumatol 4:473–480CrossRefPubMedGoogle Scholar
  18. 18.
    Fernández-Torres J, Hernández-Díaz C, Espinosa-Morales R, Camacho-Galindo J, Galindo-Sevilla N, López-Macay A et al (2015) Polymorphic variation of hypoxia inducible factor-1 A (HIF1A) gene might contribute to the development of knee osteoarthritis: a pilot study. BMC Musculoskelet Disord 16:218CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Su SL, Yang HY, Lee HS, Huang GS, Lee CH, Liu WS et al (2015) Gene–gene interactions between TGF-β/Smad3 signaling pathway polymorphisms affect susceptibility to knee osteoarthritis. BMJ Open 5(6):e007931CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K et al (1986) The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the knee. Diagnostic and therapeutic criteria committee of the American Rheumatism Association. Arthritis Rheum 29:1039–1049CrossRefPubMedGoogle Scholar
  21. 21.
    Bellamy N, Buchanan WW, Goldsmith CH (1988) Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in Patients with osteoarthritis of the hip or knee. J Rheumatol 15:1833–1840PubMedGoogle Scholar
  22. 22.
    Lequesne MG, Mery C, Samson M, Gerard P (1987) Indexes of severity for osteoarthritis of the hip and knee. Validation—valuein comparison with other assessment test. Scand J Rheumatol 65:85–89CrossRefGoogle Scholar
  23. 23.
    Moon S, Keam B, Yeong Hwang M, Lee Y, Park S et al (2015) A genome-wide association study of copy-number variation identifies putative loci associated with osteoarthritis in Koreans. BMC Musculoskelet Disord 16:76CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Rodriguez-Fontenla C, Calaza M, Evangelou E, Valdes AM, Arden N, Blanco FJ, Carr A et al (2014) Assessment of osteoarthritis candidate genes in a meta-analysis of nine genome-wide association studies. Arthritis Rheumatol 66:940–949CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Wang T, Liang Y, Li H, Li H, He Q, Xue Y et al (2016) Single nucleotide polymorphisms and osteoarthritis: an overview and a meta-analysis. Medicine (Baltimore) 95(7):e2811CrossRefGoogle Scholar
  26. 26.
    Choundry S, Coyle NE, Tang H, Salari K, Lind D, Clark SL et al (2006) Population stratification confounds genetic association studies among Latinos. Hum Genet 118(5):652–664CrossRefGoogle Scholar
  27. 27.
    Bonilla C, Parra EJ, Pfaff CL, Dios S, Marshall JA, Hamman RF et al (2004) Admixture in the Hispanics of the San Luis Valley, Colorado, and its implications for complex trait gene mapping. Ann Hum Genet 68(Pt 2):139–152CrossRefPubMedGoogle Scholar
  28. 28.
    The 1000 Genomes Project Consortium (2015) A global reference for human genetic variation. Nature 526:68–74CrossRefPubMedCentralGoogle Scholar
  29. 29.
    Ramasamy RK, Ramasamy S, Bindroo BB, Girish Naik V (2014) STRUCTURE PLOT: a program for drawing elegant STRUCTURE bar plots in user friendly interface. Springerplus 3:431CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Smith MR (2017) Ternary: an R package for creating ternary plots. Zenodo. CrossRefGoogle Scholar
  31. 31.
    Blanco FJ, Möller I, Romera M, Rozadilla A, Sánchez-Lázaro JA, Rodríguez A et al (2015) Improved prediction of knee osteoarthritis by genetic polymorphisms: the Arthrotest Study. Rheumatology 54:1236–1243CrossRefPubMedGoogle Scholar
  32. 32.
    Chapman K, Valdes AM (2012) Genetic factors in OA pathogenesis. Bone 51(2):258–264CrossRefPubMedGoogle Scholar
  33. 33.
    Luyten F, Tylzanowski P, Lories RJ (2009) Wnt signaling and osteoarthritis. Bone 44:522–527CrossRefPubMedGoogle Scholar
  34. 34.
    Velasco J, Zarrabeitia MT, Prieto JR, Perez-Castrillon JL, Perez-Aguilar MD, Perez-Nuñez MI et al (2010) Wnt pathway genes in osteoporosis and osteoarthritis: differential expression and genetic association study. Osteoporos Int 21:109–118CrossRefPubMedGoogle Scholar
  35. 35.
    Kerkhof JM, Uitterlinden AG, Valdes AM, Hart DJ, Rivadeneira F, Jhamai M et al (2008) Radiographic osteoarthritis at three joint sites and FRZB, LRP5, and LRP6 polymorphisms in two population-based cohorts. Osteoarthr Cartil 16:1141–1149CrossRefPubMedGoogle Scholar
  36. 36.
    Correa-Rodríguez M, Schmidt-RioValle J, Rueda-Medina B (2016) The rs3736228 polymorphism in the LRP5 gene is associated with calcaneal ultrasound parameter but not with body composition in a cohort of young Caucasian adults. J Bone Miner Metab 35:694–700CrossRefPubMedGoogle Scholar
  37. 37.
    Lian G, Dettenhofer M, Lu J, Downing M, Chenn A, Wong T et al (2016) Filamin A- and formin 2-dependent endocytosis regulates proliferation via the canonical Wnt pathway. Development 143:4509–4520CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    van den Bosch MH, Blom AB, van de Loo FA, Koenders MI, Lafeber FP, van den Berg WB, van der Kraan PM, van Lent PL (2017) Brief report: induction of matrix metalloproteinase expression by synovial Wnt signaling and association with disease progression in early symptomatic osteoarthritis. Arthritis Rheumatol 69:1978–1983CrossRefPubMedGoogle Scholar
  39. 39.
    Min JL, Meulenbelt I, Riyazi N, Kloppenburg M, Houwing-Duistermaat JJ, Seymour AB et al (2005) Association of the frizzled-related protein gene with symptomatic osteoarthritis at multiple sites. Arthritis Rheum 52:1077–1080CrossRefPubMedGoogle Scholar
  40. 40.
    Loughlin J, Dowling B, Chapman K, Marcelline L, Mustafa Z, Southam L et al (2004) Functional variants within the secreted frizzled related protein 3 gene are associated with hip osteoarthritis in females. Proc Natl Acad Sci USA 101:9757–9762CrossRefPubMedGoogle Scholar
  41. 41.
    Raine EVA, Dodd AW, Reynard LN, Loughlin J (2013) Allelic expression analysis of the osteoarthritis susceptibility gene COL11A1 in human joint tissues. BMC Musculoskelet Disord 14:85CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Wang J, Zhang C, Wu SG, Shang C, Huang L, Zhang T et al (2017) Additional evidence supports association of common variants in COL11A1 with increased risk of hip osteoarthritis susceptibility. Genet Test Mol Biomark 21:86–91CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  1. 1.Synovial Fluid LaboratoryInstituto Nacional de Rehabilitación “Luis Guillermo Ibarra Ibarra”Mexico CityMexico
  2. 2.Center for Research in Infectious DiseasesNational Institute of Respiratory DiseasesMexico CityMexico
  3. 3.Rheumatic and Musculoskeletal Diseases DivisionInstituto Nacional de Rehabilitación “Luis Guillermo Ibarra Ibarra”Mexico CityMexico
  4. 4.Departamento de Biología Molecular y Genómica, Instituto de Investigación en Ciencias Biomédicas (IICB)Universidad de GuadalajaraGuadalajaraMexico

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