Skip to main content

Advertisement

SpringerLink
Log in

Dual function of β-catenin in articular cartilage growth and degeneration at different stages of postnatal cartilage development

  • Original Paper
  • Published:
International Orthopaedics Aims and scope Submit manuscript

Abstract

Purpose

The objective of this study was to determine the role of β-catenin in normal postnatal articular cartilage growth and degeneration.

Methods

We investigated β-catenin gene and protein expression in hip cartilage cells of normal Wistar rats at two, four, six and eight weeks of age by using reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. Primary articular chondrocytes from eight week old rats were cultured and treated with LiCl for activation of β-catenin. Collagen X and matrix metalloproteinase 13 (MMP-13) were detected by quantitative RT-PCR and immunofluorescence. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 and 5 were detected by quantitative RT-PCR, and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) was used for detecting cell apoptosis.

Results

The highest levels of β-catenin expressions were detected in two week old rats, after which a steady decline was observed over the remaining period of observation (p < 0.05). When primary articular chondrocytes from eight week old rats were treated with LiCl, β-catenin mRNA and protein were induced (p < 0.05). Moreover, LiCl-activated β-catenin in chondrocytes was associated with significant concomitant increases in mRNA expression of collagen X and the MMP-13 encoding collagenase 3. Significantly increased mRNA expression of ADAMTS-5 was also seen in primary chondrocytes from eight week old rats after LiCl treatment (p < 0.05). The effect was specific to ADAMTS-5 since ADAMTS-4, which has similar proteolytic activity but different aggrecanase activity, was unaffected. Finally, TUNEL staining revealed that LiCl-activated β-catenin signalling led to increased cell apoptotic events in chondrocytes (p < 0.05).

Conclusions

Our findings suggest that normal spatiotemporal patterns and degrees of Wnt/β-catenin signalling are needed to maintain postnatal articular cartilage growth and function. In the early stages of cartilage development, activation of β-catenin signalling is necessary for articular cartilage growth, while in adult cartilage it leads to degeneration and osteoarthritic-like chondrocytes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Martel-Pelletier J, Boileau C, Pelletier J, Roughley P (2008) Cartilage in normal and osteoarthritis conditions. Best Pract Res Clin Rheumatol 22(2):351–384

    Article  PubMed  CAS  Google Scholar 

  2. Goldring MB, Goldring SR (2007) Osteoarthritis. J Cell Physiol 213(3):626–634

    Article  PubMed  CAS  Google Scholar 

  3. da Silva MA, Yamada N, Clarke NM, Roach HI (2009) Cellular and epigenetic features of a young healthy and a young osteoarthritic cartilage compared with aged control and OA cartilage. J Orthop Res 27(5):593–601

    Article  PubMed  Google Scholar 

  4. Brandt KD, Dieppe P, Radin EL (2008) Etiopathogenesis of osteoarthritis. Rheum Dis Clin North Am 34(3):531–559

    Article  PubMed  Google Scholar 

  5. Yano F, Kugimiya F, Ohba S, Ikeda T, Chikuda H, Ogasawara T, Ogata N, Takato T, Nakamura K, Kawaguchi H (2005) The canonical Wnt signaling pathway promotes chondrocyte differentiation in a Sox9-dependent manner. Biochem Biophys Res Commun 333(4):1300–1308

    Article  PubMed  CAS  Google Scholar 

  6. Hill TP, Spater D, Taketo MM, Birchmeier W, Hartmann C (2005) Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell 8(5):727–738

    Article  PubMed  CAS  Google Scholar 

  7. Yuasa T, Otani T, Koike T, Iwamoto M, Enomoto-Iwamoto M (2008) Wnt/β-catenin signaling stimulates matrix catabolic genes and activity in articular chondrocytes: its possible role in joint degeneration. Lab Invest 88(3):264–274

    Article  PubMed  CAS  Google Scholar 

  8. Tamamura Y, Otani T, Kanatani N, Koyama E, Kitagaki J, Komori T, Yamada Y, Costantini F, Wakisaka S, Pacifici M, Iwamoto M, Enomoto-Iwamoto M (2005) Developmental regulation of Wnt/beta-catenin signals is required for growth plate assembly, cartilage integrity, and endochondral ossification. J Biol Chem 280(19):19185–19195

    Article  PubMed  CAS  Google Scholar 

  9. Kronenberg HM (2003) Developmental regulation of the growth plate. Nature 423(6937):332–336

    Article  PubMed  CAS  Google Scholar 

  10. Day TF, Guo X, Garrett-Beal L, Yang Y (2005) Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell 8(5):739–750

    Article  PubMed  CAS  Google Scholar 

  11. Akiyama H, Lyons JP, Mori-Akiyama Y, Yang X, Zhang R, Zhang Z, Deng JM, Taketo MM, Nakamura T, Behringer RR, McCrea PD, de Crombrugghe B (2004) Interactions between Sox9 and beta-catenin control chondrocyte differentiation. Genes Dev 18(9):1072–1087

    Article  PubMed  CAS  Google Scholar 

  12. Chen M, Zhu M, Awad H, Li TF, Sheu TJ, Boyce BF, Chen D, O’Keefe RJ (2008) Inhibition of beta-catenin signaling causes defects in postnatal cartilage development. J Cell Sci 121(Pt 9):1455–1465

    Article  PubMed  CAS  Google Scholar 

  13. Zhu M, Tang D, Wu Q, Hao S, Chen M, Xie C, Rosier RN, O’Keefe RJ, Zuscik M, Chen D (2009) Activation of beta-catenin signaling in articular chondrocytes leads to osteoarthritis-like phenotype in adult beta-catenin conditional activation mice. J Bone Miner Res 24(1):12–21

    Article  PubMed  CAS  Google Scholar 

  14. Papathanasiou I, Malizos KN, Tsezou A (2010) Low-density lipoprotein receptor-related protein 5 (LRP5) expression in human osteoarthritic chondrocytes. J Orthop Res 28(3):348–353

    PubMed  CAS  Google Scholar 

  15. Blom AB, Brockbank SM, van Lent PL, van Beuningen HM, Geurts J, Takahashi N, van der Kraan PM, van de Loo FA, Schreurs BW, Clements K, Newham P, van den Berg WB (2009) Involvement of the Wnt signaling pathway in experimental and human osteoarthritis: prominent role of Wnt-induced signaling protein 1. Arthritis Rheum 60(2):501–512

    Article  PubMed  CAS  Google Scholar 

  16. Jones SE, Jomary C (2002) Secreted Frizzled-related proteins: searching for relationships and patterns. Bioessays 24(9):811–820

    Article  PubMed  CAS  Google Scholar 

  17. Lories RJ, Peeters J, Bakker A, Tylzanowski P, Derese I, Schrooten J, Thomas JT, Luyten FP (2007) Articular cartilage and biomechanical properties of the long bones in Frzb-knockout mice. Arthritis Rheum 56(12):4095–4103

    Article  PubMed  CAS  Google Scholar 

  18. Clevers H (2006) Wnt/beta-catenin signaling in development and disease. Cell 127(3):469–480

    Article  PubMed  CAS  Google Scholar 

  19. Li J, Khavandgar Z, Lin SH, Murshed M (2011) Lithium chloride attenuates BMP-2 signaling and inhibits osteogenic differentiation through a novel WNT/GSK3- independent mechanism. Bone 48(2):321–331

    Article  PubMed  CAS  Google Scholar 

  20. Hiyama A, Sakai D, Risbud MV, Tanaka M, Arai F, Abe K, Mochida J (2010) Enhancement of intervertebral disc cell senescence by WNT/beta-catenin signaling-induced matrix metalloproteinase expression. Arthritis Rheum 62(10):3036–3047

    Article  PubMed  CAS  Google Scholar 

  21. Yano F, Kugimiya F, Ohba S, Ikeda T, Chikuda H, Ogasawara T, Ogata N, Takato T, Nakamura K, Kawaguchi H, Chung UI (2005) The canonical Wnt signaling pathway promotes chondrocyte differentiation in a Sox9-dependent manner. Biochem Biophys Res Commun 333(4):1300–1308

    Article  PubMed  CAS  Google Scholar 

  22. Wu Q, Zhu M, Rosier RN, Zuscik MJ, O’Keefe RJ, Chen D (2010) β-catenin, cartilage, and osteoarthritis. Ann N Y Acad Sci 1192(1):344–350

    Article  PubMed  CAS  Google Scholar 

  23. Wu Q, Huang JH, Sampson ER, Kim K-O, Zuscik MJ, O’Keefe RJ, Chen D, Rosier RN (2009) Smurf2 induces degradation of GSK-3β and upregulates β-catenin in chondrocytes: a potential mechanism for Smurf2-induced degeneration of articular cartilage. Exp Cell Res 315(14):2386–2398

    Article  PubMed  CAS  Google Scholar 

  24. Borovecki F, Pecina-Slaus N, Vukicevic S (2007) Biological mechanisms of bone and cartilage remodelling–genomic perspective. Int Orthop 31(6):799–805

    Article  PubMed  CAS  Google Scholar 

  25. Loughlin J (2002) Genome studies and linkage in primary osteoarthritis. Rheum Dis Clin North Am 28(1):95–109

    Article  PubMed  Google Scholar 

  26. Spector TD, MacGregor AJ (2004) Risk factors for osteoarthritis: genetics. Osteoarthritis Cartilage 12 Suppl A:S39–S44

  27. Yuasa T, Kondo N, Yasuhara R, Shimono K, Mackem S, Pacifici M, Iwamoto M, Enomoto-Iwamoto M (2009) Transient activation of Wnt/{beta}-catenin signaling induces abnormal growth plate closure and articular cartilage thickening in postnatal mice. Am J Pathol 175(5):1993–2003

    Article  PubMed  CAS  Google Scholar 

  28. Dao DY, Yang X, Flick LM, Chen D, Hilton MJ, O’Keefe RJ (2010) Axin2 regulates chondrocyte maturation and axial skeletal development. J Orthop Res 28(1):89–95

    PubMed  CAS  Google Scholar 

  29. Walker GD, Fischer M, Gannon J, Thompson RC Jr, Oegema TR Jr (1995) Expression of type-X collagen in osteoarthritis. J Orthop Res 13(1):4–12

    Article  PubMed  CAS  Google Scholar 

  30. Cancel M, Grimard G, Thuillard-Crisinel D, Moldovan F, Villemure I (2009) Effects of in vivo static compressive loading on aggrecan and type II and X collagens in the rat growth plate extracellular matrix. Bone 44(2):306–315

    Article  PubMed  CAS  Google Scholar 

  31. Meyer RA Jr, Meyer MH, Ashraf N, Frick S (2007) Changes in mRNA gene expression during growth in the femoral head of the young rat. Bone 40(6):1554–1564

    Article  PubMed  CAS  Google Scholar 

  32. Kirsch T, Swoboda B, Nah H (2000) Activation of annexin II and V expression, terminal differentiation, mineralization and apoptosis in human osteoarthritic cartilage. Osteoarthritis Cartilage 8(4):294–302

    Article  PubMed  CAS  Google Scholar 

  33. Orlandi A, Oliva F, Taurisano G, Candi E, Di Lascio A, Melino G, Spagnoli LG, Tarantino U (2008) Transglutaminase-2 differently regulates cartilage destruction and osteophyte formation in a surgical model of osteoarthritis. Amino Acids 36(4):755–763

    Article  PubMed  Google Scholar 

  34. Moldovan F, Pelletier JP, Hambor J, Cloutier JM, Martel-Pelletier J (1997) Collagenase-3 (matrix metalloprotease 13) is preferentially localized in the deep layer of human arthritic cartilage in situ: in vitro mimicking effect by transforming growth factor beta. Arthritis Rheum 40(9):1653–1661

    Article  PubMed  CAS  Google Scholar 

  35. Wang X, Manner PA, Horner A, Shum L, Tuan RS, Nuckolls GH (2004) Regulation of MMP-13 expression by RUNX2 and FGF2 in osteoarthritic cartilage. Osteoarthritis Cartilage 12(12):963–973

    Article  PubMed  Google Scholar 

  36. Plaas A, Osborn B, Yoshihara Y, Bai Y, Bloom T, Nelson F, Mikecz K, Sandy JD (2007) Aggrecanolysis in human osteoarthritis: confocal localization and biochemical characterization of ADAMTS5-hyaluronan complexes in articular cartilages. Osteoarthritis Cartilage 15(7):719–734

    Article  PubMed  CAS  Google Scholar 

  37. Stanton H, Rogerson FM, East CJ, Golub SB, Lawlor KE, Meeker CT, Little CB, Last K, Farmer PJ, Campbell IK, Fourie AM, Fosang AJ (2005) ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature 434(7033):648–652

    Article  PubMed  CAS  Google Scholar 

  38. Malfait AM, Ritchie J, Gil AS, Austin JS, Hartke J, Qin W, Tortorella MD, Mogil JS (2010) ADAMTS-5 deficient mice do not develop mechanical allodynia associated with osteoarthritis following medial meniscal destabilization. Osteoarthritis Cartilage 18(4):572–580

    Article  PubMed  CAS  Google Scholar 

  39. Glasson SS, Askew R, Sheppard B, Carito B, Blanchet T, Ma HL, Flannery CR, Peluso D, Kanki K, Yang Z, Majumdar MK, Morris EA (2005) Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434(7033):644–648

    Article  PubMed  CAS  Google Scholar 

  40. Zhong M, Carney DH, Jo H, Boyan BD, Schwartz Z (2011) Inorganic phosphate induces mammalian growth plate chondrocyte apoptosis in a mitochondrial pathway involving nitric oxide and JNK MAP kinase. Calcif Tissue Int 88(2):96–108

    Article  PubMed  CAS  Google Scholar 

  41. Zhu M, Chen M, Zuscik M, Wu Q, Wang YJ, Rosier RN, O’Keefe RJ, Chen D (2008) Inhibition of beta-catenin signaling in articular chondrocytes results in articular cartilage destruction. Arthritis Rheum 58(7):2053–2064

    Article  PubMed  CAS  Google Scholar 

  42. Guo H, Luo Q, Zhang J, Lin H, Xia L, He C (2011) Comparing different physical factors on serum TNF-alpha levels, chondrocyte apoptosis, caspase-3 and caspase-8 expression in osteoarthritis of the knee in rabbits. Joint Bone Spine. Epub ahead of print

Download references

Author information

Authors and Affiliations

  1. Department of Pediatric Orthopaedics, Children’s Hospital of Fudan University, 399 Wanyuan Road, 201102, Shanghai, China

    Bo Ning, Peng Wang, Xinghong Pei, Yingquan Kang, Jun Song, Dahui Wang, Wanglin Zhang & Ruixue Ma

Authors
  1. Bo Ning
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xinghong Pei
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yingquan Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jun Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dahui Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wanglin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ruixue Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ruixue Ma.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ning, B., Wang, P., Pei, X. et al. Dual function of β-catenin in articular cartilage growth and degeneration at different stages of postnatal cartilage development. International Orthopaedics (SICOT) 36, 655–664 (2012). https://doi.org/10.1007/s00264-011-1315-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00264-011-1315-6

Keywords

Search

Navigation