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Beta-catenin Mediates Soft Tissue Contracture in Clubfoot

  • Symposium: Clubfoot: Etiology and Treatment
  • Published:
Clinical Orthopaedics and Related Research

Abstract

The contracted tissues from clubfeet resemble tissues from other fibroproliferative disorders such as palmar fibromatosis. Beta-catenin-mediated signaling is a crucial pathway controlling the fibroproliferative response in many fibroproliferative disorders. To determine if beta-catenin signaling plays a role in clubfoot, contracted and less contracted tissues from clubfeet were studied using Western analysis to determine the protein level of beta-catenin. Primary cell cultures were established from these tissues, and they were treated with either lithium to increase beta-catenin or Dickkopf-1 to inhibit beta-catenin. RNA was extracted from the cells and analyzed to determine how beta-catenin regulates expression of Type III collagen, an extracellular matrix protein upregulated in contracted clubfoot tissue. There was a more than twofold increase in beta-catenin protein in the contracted tissues. Treatment with either lithium or Dickkopf-1 showed Type III collagen RNA expression positively correlated with the protein level of beta-catenin. These data support the concept that beta-catenin-mediated signaling plays an important role regulating contracture in clubfeet. Because pharmacologic agents are under development to block this signaling pathway, such drugs could be used in cases of severe stiffness to improve range of motion or to decrease the need for radical surgical approaches.

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References

  1. Alman BA, Li C, Pajerski ME, Diaz-Cano S, Wolfe HJ. Increased beta-catenin protein and somatic APC mutations in sporadic aggressive fibromatoses (desmoid tumors). Am J Pathol. 1997;151:329–334.

    PubMed  CAS  Google Scholar 

  2. Bowley E, O’Gorman DB, Gan BS. Beta-catenin signaling in fibroproliferative disease. J Surg Res. 2007;138:141–150.

    Article  PubMed  CAS  Google Scholar 

  3. Cardy AH, Barker S, Chesney D, Sharp L, Maffulli N, Miedzybrodzka Z. Pedigree analysis and epidemiological features of idiopathic congenital talipes equinovarus in the United Kingdom: a case-control study. BMC Musculoskelet Disord. 2007;8:62.

    Article  PubMed  CAS  Google Scholar 

  4. Chen Y, Whetstone HC, Lin AC, Nadesan P, Wei Q, Poon R, Alman BA. Beta-catenin signaling plays a disparate role in different phases of fracture repair: implications for therapy to improve bone healing. PLoS Medicine. 2007;4:e249.

    Article  PubMed  Google Scholar 

  5. Chen Y, Whetstone HC, Youn A, Nadesan P, Chow EC, Lin AC, Alman BA. Beta-catenin signaling pathway is crucial for bone morphogenetic protein 2 to induce new bone formation. J Biol Chem. 2007;282:526–533.

    Article  PubMed  CAS  Google Scholar 

  6. Cheon S, Poon R, Yu C, Khoury M, Shenker R, Fish J, Alman BA. Prolonged beta-catenin stabilization and tcf-dependent transcriptional activation in hyperplastic cutaneous wounds. Lab Invest. 2005;85:416–425.

    Article  PubMed  CAS  Google Scholar 

  7. Cheon SS, Cheah AY, Turley S, Nadesan P, Poon R, Clevers H, Alman BA. beta-Catenin stabilization dysregulates mesenchymal cell proliferation, motility, and invasiveness and causes aggressive fibromatosis and hyperplastic cutaneous wounds. Proc Natl Acad Sci U S A. 2002;99:6973–6978.

    Article  PubMed  CAS  Google Scholar 

  8. Cheon SS, Nadesan P, Poon R, Alman BA. Growth factors regulate beta-catenin-mediated TCF-dependent transcriptional activation in fibroblasts during the proliferative phase of wound healing. Exp Cell Res. 2004;293:267–274.

    Article  PubMed  CAS  Google Scholar 

  9. Cheon SS, Wei Q, Gurung A, Youn A, Bright T, Poon R, Whetstone H, Guha A, Alman BA. Beta-catenin regulates wound size and mediates the effect of TGF-beta in cutaneous healing. Faseb J. 2006;20:692–701.

    Article  PubMed  CAS  Google Scholar 

  10. Clevers H, van de Wetering M. TCF/LEF factor earn their wings. Trends Genet. 1997;13:485–489.

    Article  PubMed  CAS  Google Scholar 

  11. Cooper DM, Dietz FR. Treatment of idiopathic clubfoot. A thirty-year follow-up note. J Bone Joint Surg Am. 1995;77:1477–1489.

    PubMed  CAS  Google Scholar 

  12. Dasu MR, Hawkins HK, Barrow RE, Xue H, Herndon DN. Gene expression profiles from hypertrophic scar fibroblasts before and after IL-6 stimulation. J Pathol. 2004;202:476–485.

    Article  PubMed  CAS  Google Scholar 

  13. Dietz FR, Cole WG, Tosi LL, Carroll NC, Werner RD, Comstock D, Murray JC. A search for the gene(s) predisposing to idiopathic clubfoot. Clin Genet. 2005;67:361–362.

    Article  PubMed  CAS  Google Scholar 

  14. Dihlmann S, von Knebel Doeberitz M. Wnt/beta-catenin-pathway as a molecular target for future anti-cancer therapeutics. Int J Cancer. 2005;113:515–524.

    Article  PubMed  CAS  Google Scholar 

  15. Dobbs MB, Nunley R, Schoenecker PL. Long-term follow-up of patients with clubfeet treated with extensive soft-tissue release. J Bone Joint Surg Am. 2006;88:986–996.

    Article  PubMed  Google Scholar 

  16. Eikmans M, Baelde HJ, de Heer E, Bruijn JA. Effect of age and biopsy site on extracellular matrix mRNA and protein levels in human kidney biopsies. Kidney Int. 2001;60:974–981.

    Article  PubMed  CAS  Google Scholar 

  17. Eisinger AL, Nadauld LD, Shelton DN, Prescott SM, Stafforini DM, Jones DA. Retinoic acid inhibits beta-catenin through suppression of Cox-2: a role for truncated adenomatous polyposis coli. J Biol Chem. 2007;282:29394–29400.

    Article  PubMed  CAS  Google Scholar 

  18. Fukuhara K, Schollmeier G, Uhthoff HK. The pathogenesis of club foot. A histomorphometric and immunohistochemical study of fetuses. J Bone Joint Surg Br. 1994;76:450–457.

    PubMed  CAS  Google Scholar 

  19. Herceg MB, Weiner DS, Agamanolis DP, Hawk D. Histologic and histochemical analysis of muscle specimens in idiopathic talipes equinovarus. J Pediatr Orthop. 2006;26:91–93.

    Article  PubMed  Google Scholar 

  20. Hoffman J, Kuhnert F, Davis CR, Kuo CJ. Wnts as essential growth factors for the adult small intestine and colon. Cell Cycle. 2004;3:554–557.

    PubMed  CAS  Google Scholar 

  21. Howard JC, Varallo VM, Ross DC, Roth JH, Faber KJ, Alman B, Gan BS. Elevated levels of beta-catenin and fibronectin in three-dimensional collagen cultures of Dupuytren’s disease cells are regulated by tension in vitro. BMC Musculoskelet Disord. 2003;4:16.

    Article  PubMed  Google Scholar 

  22. Kranicz J, Trombitas K, Szabo G. Results of ultrastructural analysis of the calf muscles in clubfoot. Orthopedics. 1991;14:73–75.

    PubMed  CAS  Google Scholar 

  23. Laaveg SJ, Ponseti IV. Long-term results of treatment of congenital club foot. J Bone Joint Surg Am. 1980;62:23–31.

    PubMed  CAS  Google Scholar 

  24. Li C, Bapat B, Alman BA. Adenomatous polyposis coli gene mutation alters proliferation through its beta-catenin-regulatory function in aggressive fibromatosis (desmoid tumor). Am J Pathol. 1998;153:709–714.

    PubMed  CAS  Google Scholar 

  25. Li C, Nguyen Q, Cole WG, Alman BA. Potential treatment for clubfeet based on growth factor blockade. J Pediatr Orthop. 2001;21:372–377.

    Article  PubMed  CAS  Google Scholar 

  26. Liu G, Inglis J, Cardy A, Shaw D, Sahota S, Hennekam R, Sharp L, Miedzybrodzka Z. Variation in WNT7A is unlikely to be a cause of familial congenital talipes equinovarus. BMC Med Genet. 2008;9:50.

    Article  PubMed  CAS  Google Scholar 

  27. Lochmiller C, Johnston D, Scott A, Risman M, Hecht JT. Genetic epidemiology study of idiopathic talipes equinovarus. Am J Med Genet. 1998;79:90–96.

    Article  PubMed  CAS  Google Scholar 

  28. Lustig B, Behrens J. The Wnt signaling pathway and its role in tumor development. J Cancer Res Clin Oncol. 2003;129:199–221.

    PubMed  CAS  Google Scholar 

  29. Luu HH, Zhang R, Haydon RC, Rayburn E, Kang Q, Si W, Park JK, Wang H, Peng Y, Jiang W, He TC. Wnt/beta-catenin signaling pathway as a novel cancer drug target. Curr Cancer Drug Targets. 2004;4:653–671.

    Article  PubMed  CAS  Google Scholar 

  30. Montgomery E, Lee JH, Abraham SC, Wu TT. Superficial fibromatoses are genetically distinct from deep fibromatoses. Mod Pathol. 2001;14:695–701.

    Article  PubMed  CAS  Google Scholar 

  31. Moon RT, Bowerman B, Boutros M, Perrimon N. The promise and perils of Wnt signaling through beta-catenin. Science. 2002;296:1644–1646.

    Article  PubMed  CAS  Google Scholar 

  32. Morcuende JA, Abbasi D, Dolan LA, Ponseti IV. Results of an accelerated Ponseti protocol for clubfoot. J Pediatr Orthop. 2005;25:623–626.

    Article  PubMed  Google Scholar 

  33. Murrell GA, Francis MJ, Bromley L. The collagen changes of Dupuytren’s contracture. J Hand Surg [Br]. 1991;16:263–266.

    CAS  Google Scholar 

  34. Ponseti IV. Treatment of congenital club foot. J Bone Joint Surg Am. 1992;74:448–454.

    PubMed  CAS  Google Scholar 

  35. Randomised trial to assess safety and fetal outcome of early and midtrimester amniocentesis. The Canadian Early and Mid-trimester Amniocentesis Trial (CEMAT) Group. Lancet. 1998;351:242–247.

    Article  Google Scholar 

  36. Sano H, Uhthoff HK, Jarvis JG, Mansingh A, Wenckebach GF. Pathogenesis of soft-tissue contracture in club foot. J Bone Joint Surg Br. 1998;80:641–644.

    Article  PubMed  CAS  Google Scholar 

  37. Satish L, Laframboise WA, O’Gorman DB, Johnson S, Janto B, Gan BS, Baratz ME, Hu FZ, Post JC, Ehrlich GD, Kathju S. Identification of differentially expressed genes in fibroblasts derived from patients with Dupuytren’s contracture. BMC Med Genomics. 2008;1:10.

    Article  PubMed  Google Scholar 

  38. Sato M. Upregulation of the Wnt/beta-catenin pathway induced by transforming growth factor-beta in hypertrophic scars and keloids. Acta Derm Venereol. 2006;86:300–307.

    Article  PubMed  CAS  Google Scholar 

  39. Shapiro F, Glimcher MJ. Gross and histological abnormalities of the talus in congenital club foot. J Bone Joint Surg Am. 1979;61:522–530.

    PubMed  CAS  Google Scholar 

  40. Shukla S, MacLennan GT, Flask CA, Fu P, Mishra A, Resnick MI, Gupta S. Blockade of beta-catenin signaling by plant flavonoid apigenin suppresses prostate carcinogenesis in TRAMP mice. Cancer Res. 2007;67:6925–6935.

    Article  PubMed  CAS  Google Scholar 

  41. Smalley MJ, Dale TC. Wnt signalling in mammalian development and cancer. Cancer Metastasis Rev. 1999;18:215–230.

    Article  PubMed  CAS  Google Scholar 

  42. Tejpar S, Nollet F, Li C, Wunder JS, Michils G, dal Cin P, Van Cutsem E, Bapat B, van Roy F, Cassiman JJ, Alman BA. Predominance of beta-catenin mutations and beta-catenin dysregulation in sporadic aggressive fibromatosis (desmoid tumor). Oncogene. 1999;18:6615–6620.

    Article  PubMed  CAS  Google Scholar 

  43. Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, Shaughnessy JD Jr. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med. 2003;349:2483–2494.

    Article  PubMed  CAS  Google Scholar 

  44. Varallo VM, Gan BS, Seney S, Ross DC, Roth JH, Richards RS, McFarlane RM, Alman B, Howard JC. Beta-catenin expression in Dupuytren’s disease: potential role for cell-matrix interactions in modulating beta-catenin levels in vivo and in vitro. Oncogene. 2003;22:3680–3684.

    Article  PubMed  CAS  Google Scholar 

  45. Windisch G, Anderhuber F, Haldi-Brandle V, Exner GU. Additional muscle in idiopathic club foot. Eur J Pediatr Surg. 2006;16:294–296.

    Article  PubMed  CAS  Google Scholar 

  46. Wunder JS, Nielsen TO, Maki RG, O’Sullivan B, Alman BA. Opportunities for improving the therapeutic ratio for patients with sarcoma. Lancet Oncol. 2007;8:513–524.

    Article  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Division of Orthopaedic Surgery, Program in Developmental and Stem Cell Biology, Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G1X8, Canada

    Raymond Poon MSc, Catherine Li PhD & Benjamin A. Alman MD

  2. Department of Surgery, University of Toronto, Toronto, ON, Canada

    Raymond Poon MSc, Catherine Li PhD & Benjamin A. Alman MD

Authors
  1. Raymond Poon MSc
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  2. Catherine Li PhD
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  3. Benjamin A. Alman MD
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Correspondence to Benjamin A. Alman MD.

Additional information

One of the authors (BAA) has received funding from the Canadian Institutes of Health Research.

Each author certifies that his or her institution has approved the human protocol for this investigation, that all investigations were conducted in conformity with ethical principles of research, and that informed consent for participation in the study was obtained.

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Poon, R., Li, C. & Alman, B.A. Beta-catenin Mediates Soft Tissue Contracture in Clubfoot. Clin Orthop Relat Res 467, 1180–1185 (2009). https://doi.org/10.1007/s11999-008-0692-7

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  • DOI: https://doi.org/10.1007/s11999-008-0692-7

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