Journal of Molecular Medicine

, Volume 85, Issue 9, pp 985–996 | Cite as

Cellular and molecular responses in progressive pseudorheumatoid dysplasia articular cartilage associated with compound heterozygous WISP3 gene mutation

  • Hou-De Zhou
  • Yan-Hong Bu
  • Yi-Qun Peng
  • Hui Xie
  • Min Wang
  • Lin-Qing Yuan
  • Yi Jiang
  • Duo Li
  • Qi-You Wei
  • Yu-Ling He
  • Tao Xiao
  • Jiang-Dong Ni
  • Er-Yuan Liao
Original Article

Abstract

Progressive pseudorheumatoid dysplasia (PPD) is characterized by continuous degeneration and loss of articular cartilage, which has been attributed to mutations in the gene encoding WISP3. We collected a PPD family and analyzed their WISP3 genes mutation. Articular chondrocytes (ACs) were purified from the femurs of a PPD patient after hip replacement surgery. Cell growth, proliferation, and viability were examined. Gene expression profiling and analyses of matrix metalloproteinases (MMP)-1, -3, and -13 proteins were carried out using cDNA differential microarrays, real-time reverse transcriptase-polymerase chain reaction (RT-PCR), immunohistochemistry, and Western blot analysis. We found that two probands carried a deletion (840delT) mutation in maternal allele, which leads to truncated WISP3 protein missing 43 residues in C terminus; and a 1000T>C substitution in paternal allele, which was also passed on to four other members in the PPD kindred. PPD ACs were heterogeneous in size with an enhanced rate of cell proliferation and viability compared with the normal ACs. MMP-1, -3, and -13 mRNA expressions were dereased in PPD ACs. MMP-1, -3, and -13 protein levels, however, were increased in cell lysates from PPD ACs, but markedly decreased in the supernatants from cultured ACs. WISP3 mRNA expression in PPD ACs was also decreased. Our results show, for the first time, a compound heterozygous mutation of WISP3 and a series of cellular and molecular changes disturbing the endochondral ossification in this PPD patient.

Keywords

Progressive pseudorheumatoid dysplasia WISP3 Compound heterozygous mutation 

References

  1. 1.
    Al-Awadi SA, Farag TI, Naguib K, El-Khalifa MY, Cuschieri A, Hosny G, Zahran M, Al-Ansari AG (1984) Spondyloepiphyseal dysplasia tarda with progressive arthropathy. J Med Genet 21:193–196PubMedCrossRefGoogle Scholar
  2. 2.
    Ehl S, Uhl M, Berner R, Bonafe L, Superti-Furga A, Kirchhoff A (2004) Clinical, radiographic, and genetic diagnosis of progressive pseudorheumatoid dysplasia in a patient with severe polyarthropathy. Rheumatol Int 24:53–56PubMedCrossRefGoogle Scholar
  3. 3.
    Byrne PA, Rajan KT (1998) Spondylo-epiphyseal dysplasia tarda with progressive arthropathy mimicking juvenile chronic arthritis. Br J Rheumatol 37:233–234PubMedCrossRefGoogle Scholar
  4. 4.
    Liao EY, Peng YQ, Zhou HD, Mackie EJ, Li J, Hu PA, Zhou SH, Wen GB, Zhai MX, Luo XH, Wu XP, Hu PA, Ni JD, Su X, Jiang Y, Dai RC, Guo LJ, Yuan LQ, Wang M, Wang PF, Liu SP, Yang Y, Wang C, Sui GL, Fang TY (2004) Gene symbol: WISP3. Disease: spondyloepiphyseal dysplasia tarda with progressive arthropathy. Hum Genet 115:169PubMedGoogle Scholar
  5. 5.
    Dai RC, Yao XF, Yuan LQ, Xu MQ, Liao EY, Tan LH (2004) Digital speckle correlation method: a technique to evaluate the tensile property of articular cartilage. Chinese J Med 84:1265–1269Google Scholar
  6. 6.
    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 (1999) Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia. Nat Genet 23:94–98PubMedCrossRefGoogle Scholar
  7. 7.
    Sen M, Cheng YH, Goldring MB, Lotz MK, Carson DA (2004) WISP3-dependent regulation of type II collagen and aggrecan production in chondrocytes. Arthritis Rheum 50:488–497PubMedCrossRefGoogle Scholar
  8. 8.
    Mampaey S, Vanhoenacker F, Boven K, Van Hul W, De Schepper A (2000) Progressive pseudorheumatoid dysplasia. Eur Radiol 10:1832–1835PubMedCrossRefGoogle Scholar
  9. 9.
    Archik SG, Kamat RD (1990) Progressive pseudorheumatoid chondrodysplasia simulating juvenile rheumatoid arthritis. Indian J Pediatr 57:785–788, (Abstract)PubMedGoogle Scholar
  10. 10.
    Mort JS, Billington CJ (2001) Articular cartilage and changes in arthritis matrix degradation. Arthritis Res 3:337–341PubMedCrossRefGoogle Scholar
  11. 11.
    Smith GN Jr (2006) The role of collagenolytic matrix metalloproteinases in the loss of articular cartilage in osteoarthritis. Front Biosci 11:3081–3095PubMedCrossRefGoogle Scholar
  12. 12.
    Malemud CJ (2006) Matrix metalloproteinases: role in skeletal development and growth plate disorders. Front Biosci 11:1702–1715PubMedCrossRefGoogle Scholar
  13. 13.
    Aurich M, Squires GR, Reiner A, Mollenhauer JA, Kuettner KE, Poole AR, Cole AA (2005) Differential matrix degradation and turnover in early cartilage lesions of human knee and ankle joints. Arthritis Rheum 52:112–119PubMedCrossRefGoogle Scholar
  14. 14.
    Kennedy AM, Inada M, Krane SM, Christie PT, Harding B, Lopez-Otin C, Sanchez LM, Pannett AA, Dearlove A, Hartley C, Byrne MH, Reed AA, Nesbit MA, Whyte MP, Thakker RV (2005) MMP13 mutation causes spondyloepimetaphyseal dysplasia, Missouri type (SEMDMO). J Clin Invest 115:2832–2842PubMedCrossRefGoogle Scholar
  15. 15.
    Doi T, Nishida K, Matsuo M, Yoshida A, Murakami T, Inoue H (2002) Evidence of oncotic cell death and DNA fragmentation in human hypertrophic chondrocytes in chondro-osteophyte. Osteoarthritis Cartilage 10:270–276PubMedCrossRefGoogle Scholar
  16. 16.
    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 8:294–302PubMedCrossRefGoogle Scholar
  17. 17.
    Tetlow LC, Woolley DE (2003) Histamine stimulates the proliferation of human articular chondrocytes in vitro and is expressed by chondrocytes in osteoarthritic cartilage. Ann Rheum Dis 62:991–994PubMedCrossRefGoogle Scholar
  18. 18.
    Pfander D, Kortje D, Weseloh G, Swoboda B (2001) Cell proliferation in human arthrotic joint cartilage. Z Orthop Ihre Grenzgeb 139:375–381, (Abstract)PubMedCrossRefGoogle Scholar
  19. 19.
    Wu W, Mwale F, Tchetina E, Kojima T, Yasuda T, Poole AR (2001) Cartilage matrix resorption in skeletogenesis. Novartis Found Symp 232:158–166PubMedGoogle Scholar
  20. 20.
    Ortega N, Behonick D, Stickens D, Werb Z (2003) How proteases regulate bone morphogenesis. Ann N Y Acad Sci 995:109–116PubMedCrossRefGoogle Scholar
  21. 21.
    Yu Q, Cok SJ, Zeng C, Morrison AR (2003) Translational repression of human matrix metalloproteinases-13 by an alternatively spliced form of T-cell-restricted intracellular antigen-related protein (TIAR). J Biol Chem 278:1579–1584PubMedCrossRefGoogle Scholar
  22. 22.
    Lazzerini PE, Capecchi PL, Nerucci F, Fioravanti A, Chellini F, Piccini M, Bisogno S, Marcolongo R, Laghi Pasini F (2004) Simvastatin reduces MMP-3 level in interleukin 1beta stimulated human chondrocyte culture. Ann Rheum Dis 63:867–869PubMedCrossRefGoogle Scholar
  23. 23.
    Lin PM, Chen CT, Torzilli PA (2004) Increased stromelysin-1 (MMP-3), proteoglycan degradation (3B3- and 7D4) and collagen damage in cyclically load-injured articular cartilage. Osteoarthritis Cartilage 12:485–496PubMedCrossRefGoogle Scholar
  24. 24.
    Dreier R, Grassel S, Fuchs S, Schaumburger J, Bruckner P (2004) Pro-MMP-9 is a specific macrophage product and is activated by osteoarthritic chondrocytes via MMP-3 or a MT1-MMP/MMP-13 cascade. Exp Cell Res 297:303–312PubMedCrossRefGoogle Scholar
  25. 25.
    Mitchell PG, Magna HA, Reeves LM, Lopresti-Morrow LL, Yocum SA, Rosner PJ, Geoghegan KF, Hambor JE (1996) Cloning, expression, and type II collagenolytic activity of matrix metalloproteinase-13 from human osteoarthritic cartilage. J Clin Invest 97:761–768PubMedGoogle Scholar
  26. 26.
    Sasano Y, Zhu JX, Tsubota M, Takahashi I, Onodera K, Mizoguchi I, Kagayama M (2002) Gene expression of MMP8 and MMP13 during embryonic development of bone and cartilage in the rat mandible and hind limb. J Histochem Cytochem 50:325–332PubMedGoogle Scholar
  27. 27.
    sStickens D, Behonick DJ, Ortega N, Heyer B, Hartenstein B, Yu Y, Fosang AJ, Schorpp-Kistner M, Angel P, Werb Z (2004) Altered endochondral bone development in matrix metalloproteinase 13-deficient mice. Development 131:5883–5895PubMedCrossRefGoogle Scholar
  28. 28.
    Inada M, Wang Y, Byrne MH, Rahman MU, Miyaura C, Lopez-Otin C, Krane SM (2004) Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification. Proc Natl Acad Sci USA 101:17192–17197PubMedCrossRefGoogle Scholar
  29. 29.
    Schulze-Tanzil G, de Souza P, Merker HJ, Shakibaei M (2001) Co-localization of integrins and matrix metalloproteinases in the extracellular matrix of chondrocyte cultures. Histol Histopathol 16:1081–1089PubMedGoogle Scholar
  30. 30.
    Sekiya I, Vuoristo JT, Larson BL, Prockop DJ (2002) In vitro cartilage formation by human adult stem cells from bone marrow stroma defines the sequence of cellular and molecular events during chondrogenesis. Proc Natl Acad Sci USA 99:4397–4402PubMedCrossRefGoogle Scholar
  31. 31.
    Lark MW, Bayne EK, Flanagan J, Harper CF, Hoerrner LA, Hutchinson NI, Singer II, Donatelli SA, Weidner JR, Williams HR, Mumford RA, Lohmander LS (1997) Aggrecan degradation in human cartilage. Evidence for both matrix metalloproteinase and aggrecanase activity in normal, osteoarthritic, and rheumatoid joints. J Clin Invest 100:93–106PubMedCrossRefGoogle Scholar
  32. 32.
    Stahle-Backdahl M, Sandstedt B, Bruce K, Lindahl A, Jimenez MG, Vega JA, Lopez-Otin C (1997) Collagenase-3 (MMP-13) is expressed during human fetal ossification and re-expressed in postnatal bone remodeling and in rheumatoid arthritis. Lab Invest 76:717–728PubMedGoogle Scholar
  33. 33.
    Sandell LJ, Aigner T (2001) Articular cartilage and changes in arthritis. An introduction: cell biology of osteoarthritis. Arthritis Res 3:107–113PubMedCrossRefGoogle Scholar
  34. 34.
    Garnero P, Ayral X, Rousseau JC, Christgau S, Sandell LJ, Dougados M, Delmas PD (2002) Uncoupling of type II collagen synthesis and degradation predicts progression of joint damage in patients with knee osteoarthritis. Arthritis Rheum 46:2613–2624PubMedCrossRefGoogle Scholar
  35. 35.
    Hayami T, Pickarski M, Wesolowski GA, McLane J, Bone A, Destefano J, Rodan GA, Duong T (2004) The role of subchondral bone remodeling in osteoarthritis: reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model. Arthritis Rheum 50:1193–1206PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Hou-De Zhou
    • 1
  • Yan-Hong Bu
    • 1
  • Yi-Qun Peng
    • 1
  • Hui Xie
    • 1
  • Min Wang
    • 1
  • Lin-Qing Yuan
    • 1
  • Yi Jiang
    • 2
  • Duo Li
    • 2
  • Qi-You Wei
    • 2
  • Yu-Ling He
    • 1
  • Tao Xiao
    • 3
  • Jiang-Dong Ni
    • 3
  • Er-Yuan Liao
    • 1
  1. 1.Institute of Endocrinology and MetabolismThe Second Xiang-Ya Hospital of Central South UniversityChangshaChina
  2. 2.Department of PathologyThe Second Xiang-Ya Hospital of Central South UniversityChangshaChina
  3. 3.Department of OrthopaedicsThe Second Xiang-Ya Hospital of Central South UniversityChangshaChina

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