Journal of Bone and Mineral Metabolism

, Volume 25, Issue 4, pp 253–258 | Cite as

Association of a single nucleotide polymorphism in the WISP1 gene with spinal osteoarthritis in postmenopausal Japanese women

  • Tomohiko Urano
  • Ken'ichiro Narusawa
  • Masataka Shiraki
  • Takahiko Usui
  • Noriko Sasaki
  • Takayuki Hosoi
  • Yasuyoshi Ouchi
  • Toshitaka Nakamura
  • Satoshi Inoue


The Wnt-β-catenin signaling pathway that regulates bone density is also involved in cartilage development and homeostasis in vivo. Here, we assumed that genetic variation in Wnt-β-catenin signaling genes can affect the pathogenesis of cartilage related diseases, such as osteoarthritis. Wnt-1-induced secreted protein 1 (WISP1) is a target of the Wnt pathway and directly regulated by β-catenin. In the present study, we analyzed the association of a single nucleotide polymorphism (SNP) in the WISP1 3′-UTR region with the development of radiographically observable osteoarthritis of the spine. For this purpose, we evaluated the presence of osteophytes, endplate sclerosis, and narrowing of disc spaces in 304 postmenopausal Japanese women. We compared those who carried the G allele (GG or GA, n = 184) with those who did not (AA, n = 120). We found that the subjects without the G allele (AA) were significantly over-represented in the subjects having higher endplate sclerosis score (P = 0.0069; odds ratio, 2.91; 95% confidence interval, 1.34–6.30 by logistic regression analysis). On the other hand, the occurrence of disc narrowing and osteophyte formation did not significantly differ between those with and without at least one G allele. Thus, we suggest that a genetic variation in the WISP1 gene locus is associated with spinal osteoarthritis, in line with the involvement of the Wnt-β-catenin-regulated gene in bone and cartilage metabolism.

Key words

single nucleotide polymorphism (SNP) Wnt-β-catenin signaling WISP1 osteoarthritis endplate sclerosis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Creamer, P, Hochberg, MC 1997OsteoarthritisLancet350503508PubMedCrossRefGoogle Scholar
  2. 2.
    Lane, NE, Nevitt, MC, Genant, HK, Hochberg, MC 1993Reliability of new indices of radiographic osteoarthritis of the hand and hip and lumbar disc degenerationJ Rheumatol2019111918PubMedGoogle Scholar
  3. 3.
    O'Neill, TW, McCloskey, EV, Kanis, JA, Bhalla, AK, Reeve, J, Reid, DM, Todd, C, Woolf, AD, Silman, AJ 1999The distribution, determinants, and clinical correlates of vertebral osteophytosis: a population based surveyJ Rheumatol26842848PubMedGoogle Scholar
  4. 4.
    Spector, TD, MacGregor, AJ 2004Risk factors for osteoarthritis: geneticsOsteoarthritis Cartilage12S39S44PubMedCrossRefGoogle Scholar
  5. 5.
    Loughlin, J 2003Genetics of osteoarthritis and potential for drug developmentCurr Opin Pharmacol3295299PubMedCrossRefGoogle Scholar
  6. 6.
    Nusse, R, Varmus, HE 1992Wnt genesCell6910731087PubMedCrossRefGoogle Scholar
  7. 7.
    Rijsewijk, F, Schuermann, M, Wagenaar, E, Parren, P, Weigel, D, Nusse, R 1987The Drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene winglessCell50649657PubMedCrossRefGoogle Scholar
  8. 8.
    Nusse, R, Varmus, HE 1982Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genomeCell3199109PubMedCrossRefGoogle Scholar
  9. 9.
    Barrow, JR, Thomas, KR, Boussadia-Zahui, O, Moore, R, Kemier, R, Capecchi, MR, McMahon, AP 2003Ectodermal Wnt3/beta-catenin signaling is required for the establishment and maintenance of the apical ectodermal ridgeGenes Dev17394409PubMedCrossRefGoogle Scholar
  10. 10.
    Soshnikova, N, Zechner, D, Huelsken, J, Mishina, Y, Behringer, RR, Taketo, MM, Crenshaw, EB,III, Birchmeier, W 2003Genetic interaction between Wnt/beta-catenin and BMP receptor signaling during formation of the AER and the dorsal-ventral axis in the limbGenes Dev1719631968PubMedCrossRefGoogle Scholar
  11. 11.
    Cadigan, KM, Nusse, R 1999Wnt signaling: a common theme in animal developmentGenes Dev1132863305Google Scholar
  12. 12.
    Bennett, CN, Longo, KA, Wright, WS, Suva, LJ, Lane, TF, Hankenson, KD, MacDougald, OA 2005Regulation of osteoblastogenesis and bone mass by Wnt10bProc Natl Acad Sci U S A10233243329PubMedCrossRefGoogle Scholar
  13. 13.
    Bain, G, Muller, T, Wang, X, Papkoff, J 2003Activated beta-catenin induces osteoblast differentiation of C3H10T1/2 cells and participates in BMP2 mediated signal transductionBiochem Biophys Res Commun3018491PubMedCrossRefGoogle Scholar
  14. 14.
    Tamai, K, Semenov, M, Kato, Y, Spokony, R, Liu, C, Katsuyama, Y, Hess, F, Saint-Jeannet, JP, He, X 2000LDL-receptor-related proteins in Wnt signal transductionNature (Lond)407530553CrossRefGoogle Scholar
  15. 15.
    Mao, J, Wang, J, Liu, B, Pan, W, Farr, GH,III, Flynn, C, Yuan, H, Takada, S, Kimelman, D, Li, L, Wu, D 2001Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathwayMol Cell7801809PubMedCrossRefGoogle Scholar
  16. 16.
    Gong, Y, Slee, RB, Fukai, N, Rawadi, G, Roman-Roman, S,  et al. 2001LDL receptor-related protein 5 (LRP5) affects bone accrual and eye developmentCell107513523PubMedCrossRefGoogle Scholar
  17. 17.
    Kato, M, Patel, MS, Levasseur, R, Lobov, I, Chang, BH, Glass, DA,II, Hartmann, C, Li, L, Hwang, TH, Brayton, CF, Lang, RA, Karsenty, G, Chan, L 2002Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptorJ Cell Biol157303314PubMedCrossRefGoogle Scholar
  18. 18.
    Boyden, LM, Mao, J, Belsky, J, Mitzner, L, Farhi, A, Mitnick, MA, Wu, D, Insogna, K, Lifton, RP 2002High bone density due to a mutation in LDL-receptor-related protein 5N Engl J Med34615131521PubMedCrossRefGoogle Scholar
  19. 19.
    Little, RD, Carulli, JP, Del Mastro, RG, Dupuis, J, Osborne, M,  et al. 2002A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass traitAm J Hum Genet701119PubMedCrossRefGoogle Scholar
  20. 20.
    Urano, T, Shiraki, M, Ezura, Y, Fujita, M, Sekine, E, Hoshino, S, Hosoi, T, Orimo, H, Emi, M, Ouchi, Y, Inoue, S 2004Association of a single-nucleotide polymorphism in low-density lipoprotein receptor-related protein 5 gene with bone mineral densityJ Bone Miner Metab22341345PubMedCrossRefGoogle Scholar
  21. 21.
    Mizuguchi, T, Furuta, I, Watanabe, Y, Tsukamoto, K, Tomita, H, Tsujihata, M, Ohta, T, Kishino, T, Matsumoto, N, Minakami, H, Niikawa, N, Yoshiura, K 2004LRP5, low-density-lipoprotein-receptor-related protein 5, is a determinant for bone mineral densityJ Hum Genet498086PubMedCrossRefGoogle Scholar
  22. 22.
    Ferrari, SL, Deutsch, S, Choudhury, U, Chevalley, T, Bonjour, JP, Dermitzakis, ET, Rizzoli, R, Antonarakis, SE 2004Polymorphisms in the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with variation in vertebral bone mass, vertebral bone size, and stature in whitesAm J Hum Genet74866875PubMedCrossRefGoogle Scholar
  23. 23.
    Lau, HH, Ng, MY, Ho, AY, Luk, KD, Kung, AW 2005Genetic and environmental determinants of bone mineral density in Chinese womenBone (NY)36700709Google Scholar
  24. 24.
    Sen, M, Lauterbach, K, El-Gabalawy, H, Firestein, GS, Corr, M, Carson, DA 2000Expression and function of wingless and frizzled homologs in rheumatoid arthritisProc Natl Acad Sci USA9727912796PubMedCrossRefGoogle Scholar
  25. 25.
    James, IE, Kumar, S, Barnes, MR, Gress, CJ, Hand, AT, Dodds, RA, Connor, JR, Bradley, BR, Campbell, DA, Grabill, SE, Williams, K, Blake, SM, Gowen, M, Lark, MW 2000FrzB-2: a human secreted frizzled-related protein with a potential role in chondrocyte apoptosisOsteoarthritis Cartilage8452463PubMedCrossRefGoogle Scholar
  26. 26.
    Ryu, JH, Kim, SJ, Kim, SH, Oh, CD, Hwang, SG, Chun, CH, Oh, SH, Seong, JK, Huh, TL, Chun, JS 2002Regulation of the chondrocyte phenotype by beta-cateninDevelopment (Camb)12955415550CrossRefGoogle Scholar
  27. 27.
    Bork, P 1993The modular architecture of a new family of growth regulators related to connective tissue growth factorFEBS lett327125130PubMedCrossRefGoogle Scholar
  28. 28.
    Brigstock, DR 1999The connective tissue growth factor/cystein-rich 61/nephroblastoma overexpressed (CCN) familyEndcr Rev20189206CrossRefGoogle Scholar
  29. 29.
    Perbal, B 2001NOV (nephroblastoma overexpressed) and the CCN family of genes: structural and functional issuesMol Pathol545779PubMedCrossRefGoogle Scholar
  30. 30.
    Pennica, D, Swanson, TA, Welsh, JW, Roy, MA, Lawrence, DA,  et al. 1998WISP genes are members of the connective tissue growth factor family that are up-regulated in wnt-1-transformed cells and aberrantly expressed in human colon tumorsProc Natl Acad Sci USA951471714722PubMedCrossRefGoogle Scholar
  31. 31.
    Xu, L, Corcoran, RB, Welsh, JW, Pennica, D, Levine, AJ 2000WISP-1 is a Wnt-1- and beta-catenin-responsive oncogeneGenes Dev14585595PubMedGoogle Scholar
  32. 32.
    Desnoyers, L, Arnott, D, Pennica, D 2001WISP-1 binds to decorin and biglycanJ Biol Chem2764759947607PubMedCrossRefGoogle Scholar
  33. 33.
    French, DM, Kaul, RJ, D'Souza, AL, Crowley, CW, Bao, M, Frantz, GD, Filvaroff, EH, Desnoyers, L 2004WISP-1 is an osteoblastic regulator expressed during skeletal development and fracture repairAm J Pathol165855867PubMedGoogle Scholar
  34. 34.
    Yu, W, Gluer, CC, Fuerst, T, Grampp, S, Li, J, Lu, Y, Genant, HK 1995Influence of degenerative joint disease on spinal bone mineral measurements in postmenopausal womenCalcif Tissue Int57169174PubMedCrossRefGoogle Scholar
  35. 35.
    Asai, T, Ohkubo, T, Katsuya, T, Higaki, J, Fu, Y, Fukuda, M, Hozawa, A, Matsubara, M, Kitaoka, H, Tsuji, I, Araki, T, Satoh, H, Hisamichi, S, Imai, Y, Ogihara, T 2001Endothelin-1 gene variant associates with blood pressure in obese Japanese subjects: the Ohasama StudyHypertension3813211324PubMedGoogle Scholar
  36. 36.
    Baldwin, CT, Farrer, LA, Adair, R, Dharmavaram, R, Jimenez, S, Anderson, L 1995Linkage of early-onset osteoarthritis and chondrocalcinosis to human chromosome 8qAm J Hum Genet56692697PubMedGoogle Scholar
  37. 37.
    Smith, AJ, Gidley, J, Sandy, JR, Perry, MJ, Elson, CJ, Kirwan, JR, Spector, TD, Doherty, M, Bidwell, JL, Mansell, JP 2005Haplotypes of the low-density lipoprotein receptor-related protein 5 (LRP5) gene: are they a risk factor in osteoarthritis?Osteoarthritis Cartilage13608613PubMedCrossRefGoogle Scholar
  38. 38.
    Urano, T, Shiraki, M, Narusawa, K, Usui, T, Sasaki, N, Hosoi, T, Ouchi, Y, Nakamura, T, Inoue, S 2007Q89R polymorphism in the LDL receptor-related protein 5 gene is associated with spinal osteoarthritis in postmenopausal Japanese womenSpine322529PubMedCrossRefGoogle Scholar
  39. 39.
    Loughlin, J, Dowling, B, Chapman, K, Marcelline, L, Mustafa, Z, Southam, L, Ferreira, A, Ciesielski, C, Carson, DA, Corr, M 2004Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in femalesProc Natl Acad Sci USA10197579762PubMedCrossRefGoogle Scholar
  40. 40.
    Hurvitz, JR, Suwairi, WM, Van Hul, W, El-Shanti, H, Superti-Furga, A, Roudier, J, Holderbaum, D, Pauli, RM, Herd, JK, Van Hul, EV, Rezai-Delui, H, Legius, E, Le Merrer, M, Al-Alami, J, Bahabri, SA, Warman, ML 1999Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasiaNat Genet239498PubMedCrossRefGoogle Scholar
  41. 41.
    Lamb, R Thomson, W Ogilvie, E Donn, R British Society of Paediatric and Adolescent Rheumatology2005Wnt-1-inducible pathway protein 3 and susceptibility to juvenile idiopathic arthritisArthritis Rheum5235483553PubMedCrossRefGoogle Scholar
  42. 42.
    Sen, M, Cheng, YH, Goldring, MB, Lotz, MK, Carson, DA 2004WISP3-dependent regulation of type II collagen and aggrecan production in chondrocytesArthritis Rheum50488497PubMedCrossRefGoogle Scholar
  43. 43.
    Tanaka, I, Morikawa, M, Okuse, T, Shirakawa, M, Imai, K 2005Expression and regulation of WISP2 in rheumatoid arthritic synoviumBiochem Biophys Res Commun334973978PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 2007

Authors and Affiliations

  • Tomohiko Urano
    • 1
    • 2
  • Ken'ichiro Narusawa
    • 3
  • Masataka Shiraki
    • 4
  • Takahiko Usui
    • 1
  • Noriko Sasaki
    • 1
  • Takayuki Hosoi
    • 5
  • Yasuyoshi Ouchi
    • 1
  • Toshitaka Nakamura
    • 3
  • Satoshi Inoue
    • 1
    • 6
  1. 1.Department of Geriatric MedicineGraduate School of Medicine, The University of TokyoTokyoJapan
  2. 2.Department of Coca-Cola Anti-Aging MedicineGraduate School of Medicine, The University of TokyoTokyoJapan
  3. 3.Department of Orthopedic SurgeryUniversity of Occupational and Environmental Health, School of MedicineKitakyushuJapan
  4. 4.Research Institute and Practice for Involutional DiseasesNaganoJapan
  5. 5.Department of Advanced MedicineNational Center for Geriatrics and GerontologyAichiJapan
  6. 6.Research Center for Genomic MedicineSaitama Medical SchoolSaitamaJapan

Personalised recommendations