Research ArticleArticle

SMAD3 Is Upregulated in Human Osteoarthritic Cartilage Independent of the Promoter DNA Methylation

Erfan Aref-Eshghi, Ming Liu, Seyd Babak Razavi-Lopez, Kensuke Hirasawa, Patricia E. Harper, Glynn Martin, Andrew Furey, Roger Green, Guang Sun, Proton Rahman and Guangju Zhai
The Journal of Rheumatology February 2016, 43 (2) 388-394; DOI: https://doi.org/10.3899/jrheum.150609

REFERENCES

  1. 1.↵
    1. Vos T,
    2. Flaxman AD,
    3. Naghavi M,
    4. Lozano R,
    5. Michaud C,
    6. Ezzati M,
    7. et al.
    Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2163–96.
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Kean WF,
    2. Kean R,
    3. Buchanan WW
    . Osteoarthritis: Symptoms, signs and source of pain. Inflammopharmacology 2004;12:3–31.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Woolf AD,
    2. Pfleger B
    . Burden of major musculoskeletal condition — Bone and Joint Decade 2000–2010. Bull World Health Org 2003;81:646–56.
    OpenUrlPubMed
  4. 4.↵
    1. Roach HI
    . The complex pathology of osteoarthritis: Even mitochondria are involved. Arthritis Rheum 2008;58:2217–8.
    OpenUrlCrossRefPubMed
  5. 5.↵
    1. Zhai G,
    2. Aref-Eshghi E
    . Biomarkers for osteoarthritis: Investigation, identification, and prognosis. Curr Biomark Find 2012;2:19–28.
    OpenUrl
  6. 6.↵
    1. Song B,
    2. Estrada KD,
    3. Lyons KM
    . Smad signaling in skeletal development and regeneration. Cytokine Growth Factor Rev 2009;20:379–88.
    OpenUrlCrossRefPubMed
  7. 7.↵
    1. Shen J,
    2. Li S,
    3. Chen D
    . TGF-β signaling and the development of osteoarthritis. Bone Res 2014;2. pii: 14002.
    OpenUrlCrossRefPubMed
  8. 8.↵
    1. Li TF,
    2. Dowish M,
    3. Zuscik MJ,
    4. Chen D,
    5. Schwarz EM,
    6. Rosier RN,
    7. et al.
    Smad3-deficient chondrocytes have enhanced BMP signaling and accelerated differentiation. J Bone Miner Res 2006;21:4–16.
    OpenUrlCrossRefPubMed
  9. 9.↵
    1. Wu Q,
    2. Huang JH,
    3. Sampson ER,
    4. Kim KO,
    5. Zuscik MJ,
    6. O’Keefe RJ,
    7. et al.
    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 2009;315:2386–98.
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Yang X,
    2. Chen L,
    3. Xu X,
    4. Li C,
    5. Huang C,
    6. Deng CX
    . TGF-beta/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. J Cell Biol 2001;153:35–46.
    OpenUrlAbstract/FREE Full Text
  11. 11.↵
    1. Chen CG,
    2. Thuillier D,
    3. Chin EN,
    4. Alliston T
    . Chondrocyte-intrinsic Smad3 represses Runx2-inducible matrix metalloproteinase 13 expression to maintain articular cartilage and prevent osteoarthritis. Arthritis Rheum 2012;64:3278–89.
    OpenUrlCrossRefPubMed
  12. 12.↵
    1. Yao JY,
    2. Wang Y,
    3. An J,
    4. Mao CM,
    5. Hou N,
    6. Lv Y,
    7. et al.
    Mutations analysis of the SMAD3 gene in human osteoarthritis. Eur J Hum Genet 2003;11:714–7.
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Van de Laar IM,
    2. Oldenburg RA,
    3. Pals G,
    4. Roos-Hesselink JW,
    5. De Graaf BM,
    6. Verhagen JM,
    7. et al.
    Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet 2011;43:121–6.
    OpenUrlCrossRefPubMed
  14. 14.↵
    1. van de Laar IM,
    2. van der Linde D,
    3. Oei EH,
    4. Bos PK,
    5. Bessems JH,
    6. Bierma-Zeinstra SM,
    7. et al.
    Phenotypic spectrum of the SMAD3-related aneurysms–osteoarthritis syndrome. J Med Genet 2012;49:47–57.
    OpenUrlAbstract/FREE Full Text
  15. 15.↵
    1. Valdes AM,
    2. Spector TD,
    3. Tamm A,
    4. Kisand K,
    5. Doherty SA,
    6. Dennison EM,
    7. et al.
    Genetic variation in the SMAD3 gene is associated with hip and knee osteoarthritis. Arthritis Rheum 2010;62:2347–52.
    OpenUrlCrossRefPubMed
  16. 16.↵
    1. Liying J,
    2. Yuchun T,
    3. Youcheng W,
    4. Yingchen W,
    5. Chunyu J,
    6. Yanling Y,
    7. et al.
    A SMAD3 gene polymorphism is related with osteoarthritis in a Northeast Chinese population. Rheumatol Int 2013;33:1763–8.
    OpenUrlCrossRefPubMed
  17. 17.↵
    1. Aref-Eshghi E,
    2. Zhang Y,
    3. Hart D,
    4. Valdes AM,
    5. Furey A,
    6. Martin G,
    7. et al.
    SMAD3 is associated with the total burden of radiographic osteoarthritis: The Chingford Study. PLoS One 2014;9:e97786.
    OpenUrlCrossRefPubMed
  18. 18.↵
    1. Aref-Eshghi E,
    2. Rahman P,
    3. Zhang H,
    4. Martin G,
    5. Furey A,
    6. Green R,
    7. et al.
    Attempt to replicate the published osteoarthritis-associated genetic variants in the Newfoundland & Labrador population. J Orthopedics Rheumatol 2014;1:5.
    OpenUrl
  19. 19.↵
    1. Zhang W,
    2. Likhodii S,
    3. Zhang Y,
    4. Aref-Eshghi E,
    5. Harper PE,
    6. Randell E,
    7. et al.
    Classification of osteoarthritis phenotypes by metabolomics analysis. BMJ Open 2014;4:e006286.
    OpenUrlCrossRefPubMed
  20. 20.↵
    1. Altman RG,
    2. Alarcon D,
    3. Appelrouth D,
    4. Bloch D,
    5. Borenstein K,
    6. Brandt C,
    7. et al.
    The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hip. Arthritis Rheum 1991;34:505–14.
    OpenUrlCrossRefPubMed
  21. 21.↵
    1. Livak KJ,
    2. Schmittgen TD
    . Analysis of relative gene expression data using real-time quantitative PCR and the 2(−delta delta C(T)) method. Methods 2001;25:402–8.
    OpenUrlCrossRefPubMed
  22. 22.↵
    1. Ehrich M,
    2. Nelson MR,
    3. Stanssens P,
    4. Zabeau M,
    5. Liloglou T,
    6. Xinarianos G,
    7. et al.
    Quantitative high-throughput analysis of DNA methylation patterns by base-specific cleavage and mass spectrometry. Proc Natl Acad Sci USA 2005;102:15785–90.
    OpenUrlAbstract/FREE Full Text
  23. 23.↵
    1. Wu MY,
    2. Hill CS
    . TGF-β superfamily signaling in embryonic development and homeostasis. Dev Cell 2009;16:329–43.
    OpenUrlCrossRefPubMed
  24. 24.↵
    1. Wharton K,
    2. Derynck R
    . TGF-β family signaling: Novel insights in development and disease. Development 2009;136:3691–7.
    OpenUrlAbstract/FREE Full Text
  25. 25.↵
    1. Van der Kraan PM,
    2. Blaney Davidson EN,
    3. Van den Berg WB
    . A role for age-related changes in TGF-β signaling in aberrant chondrocyte differentiation and osteoarthritis. Arthritis Res Ther 2010;12:201.
    OpenUrlCrossRefPubMed
  26. 26.↵
    1. Van der Kraan PM,
    2. Blaney Davidson EN,
    3. Blom A,
    4. Van den Berg WB
    . TGF-β signaling in chondrocyte terminal differentiation and osteoarthritis: Modulation and integration of signaling pathways through receptor-Smads. Osteoarthritis Cartilage 2009;17:1539–45.
    OpenUrlCrossRefPubMed
  27. 27.↵
    1. Blaney Davidson EN,
    2. Vitters EL,
    3. Van der Kraan PM,
    4. Van den Berg WB
    . Expression of transforming growth factor-β (TGF-β) and the TGF-β signalling molecule Smad-2P in spontaneous and instability-induced osteoarthritis: Role in cartilage degradation, chondrogenesis and osteophyte formation. Ann Rheum Dis 2006;65:1414–21.
    OpenUrlAbstract/FREE Full Text
  28. 28.↵
    1. Blaney Davidson EN,
    2. Scharstuhl A,
    3. Vitters EL,
    4. Van der Kraan PM,
    5. Van den Berg WB
    . Reduced transforming growth factor-β signaling in cartilage of old mice: Role in impaired repair capacity. Arthritis Res Ther 2005;7:R1338–47.
    OpenUrlCrossRefPubMed
  29. 29.↵
    1. Busque L,
    2. Belisle C,
    3. Provost S,
    4. Giroux M,
    5. Perreault C
    . Differential expression of SMAD3 transcripts is not regulated by cis-acting genetic elements but has a gender specificity. Genes Immun 2009;10:192–6.
    OpenUrlCrossRefPubMed
  30. 30.↵
    1. Harrison MH,
    2. Shajowicz F,
    3. Trueta J
    . Osteoarthritis of the hip: A study of the nature and evolution of the disease. J Bone Joint Surg Br 1953;35:598–626.
    OpenUrlPubMed
  31. 31.↵
    1. Lajeunesse D
    . The role of bone in the treatment of osteoarthritis. Osteoarthritis Cartilage 2004;12:S34–8.
    OpenUrlCrossRefPubMed
  32. 32.↵
    1. Finnson KW,
    2. Chi Y,
    3. Bou-Gharios G,
    4. Leask A,
    5. Philip A
    . TGF-b signaling in cartilage homeostasis and osteoarthritis. Front Biosci (Schol Ed) 2012;1:251–68.
    OpenUrl
  33. 33.↵
    1. Van Beuningen HM,
    2. Glansbeek HL,
    3. Van der Kraan PM,
    4. Van den Berg WB
    . Osteoarthritis-like changes in the murine knee joint resulting from intra-articular transforming growth factor-beta injections. Osteoarthritis Cartilage 2000;8:25–33.
    OpenUrlCrossRefPubMed
  34. 34.↵
    1. Zhen G,
    2. Wen C,
    3. Jia X,
    4. Li Y,
    5. Crane JL,
    6. Mears SC,
    7. et al.
    Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. Nat Med 2013;19:704–12.
    OpenUrlCrossRefPubMed
  35. 35.↵
    1. Bakker AC,
    2. van de Loo FA,
    3. van Beuningen HM,
    4. Sime P,
    5. van Lent PL,
    6. van der Kraan PM,
    7. et al.
    Overexpression of active TGF-β1 in the murine knee joint: Evidence for synovial-layer-dependent chondro-osteophyte formation. Osteoarthritis Cartilage 2001;9:128–36.
    OpenUrlCrossRefPubMed
  36. 36.↵
    1. Moldovan F,
    2. Pelletier JP,
    3. Hambor J,
    4. Cloutier JM,
    5. Martel-Pelletier J
    . 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 1997;40:1653–61.
    OpenUrlCrossRefPubMed
  37. 37.↵
    1. Leivonen SK,
    2. Ala-Aho R,
    3. Koli K,
    4. Grénman R,
    5. Peltonen J,
    6. Kähäri VM
    . Activation of Smad signaling enhances collagenase-3 (MMP-13) expression and invasion of head and neck squamous carcinoma cells. Oncogene 2006;25:2588–600.
    OpenUrlCrossRefPubMed
  38. 38.↵
    1. Selvamurugan N,
    2. Kwok S,
    3. Partridge NC
    . Smad3 interacts with JunB and Cbfa1/Runx2 for transforming growth factor-beta1-stimulated collagenase-3 expression in human breast cancer cells. J Biol Chem 2004;279:27764–73.
    OpenUrlAbstract/FREE Full Text
  39. 39.↵
    1. Leivonen SK,
    2. Chantry A,
    3. Hakkinen L,
    4. Han J,
    5. Kahari VM
    . Smad3 mediates transforming growth factor-beta-induced collagenase-3 (matrix metalloproteinase-13) expression in human gingival fibroblasts. Evidence for cross-talk between Smad3 and p38 signaling pathways. J Biol Chem 2002;277:46338–46.
    OpenUrlAbstract/FREE Full Text
  40. 40.↵
    1. Selvamurugan N,
    2. Kwok S,
    3. Alliston T,
    4. Reiss M,
    5. Partridge NC
    . Transforming growth factor-beta 1 regulation of collagenase-3 expression in osteoblastic cells by cross-talk between the Smad and MAPK signaling pathways and their components, Smad2 and Runx2. J Biol Chem 2004;279:19327–34.
    OpenUrlAbstract/FREE Full Text
  41. 41.↵
    1. Raine EV,
    2. Reynard LN,
    3. van de Laar IM,
    4. Bertoli-Avella AM,
    5. Loughlin J
    . Identification and analysis of a SMAD3 cis-acting eQTL operating in primary osteoarthritis and in the aneurysms and osteoarthritis syndrome. Osteoarthritis Cartilage 2014;22:698–705.
    OpenUrlCrossRefPubMed
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Keywords

OSTEOARTHRITIS
CARTILAGE
SMAD3
GENE EXPRESSION
DNA METHYLATION

Keywords