Skip to main content

Advertisement

SpringerLink
Log in

TGF-β signal transduction pathways and osteoarthritis

  • Review Article - Pathology Review
  • Published:
Rheumatology International Aims and scope Submit manuscript

Abstract

Osteoarthritis (OA) is the most common form of arthritis, resulting in substantial disability and economic burden worldwide. While its exact pathogenesis remains elusive, both in vitro and human population-based studies have merged to support the hypothesis that TGF-β/BMP-mediated signalling pathways play a role in the development of OA. Unraveling the TGF-β/BMP-mediated mechanism(s) in OA has great potential in identifying novel targets and developing new drugs for OA treatment. This review summarizes both in vitro and in vivo evidence of TGF-β/BMP-mediated signal transduction pathways in OA and discusses the future research direction in this regard.

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

Similar content being viewed by others

References

  1. Paitzker K (2003) Pathology of osteoarthritis. In: Brandt K, Doherty M, Lohmander LS (eds) Osteoarthritis, 2nd edn. Oxford University Press, Oxford, pp 49–58

    Google Scholar 

  2. The burden of musculoskeletal conditions at the start of the new millennium: report of a WHO Scientific Group (2003) World Health Organisation, Geneva

  3. Reginster JY (2002) The prevalence and burden of arthritis. Rheumatology (Oxford) 41(Supp 1):3–6

    Article  Google Scholar 

  4. Bitton R (2009) The economic burden of osteoarthritis. Am J Manag Care 15(8 Suppl):S230–S235

    PubMed  Google Scholar 

  5. Felson DT (2004) An update on the pathogenesis and epidemiology of osteoarthritis. Radiol Clin N Am 42(1):1–9

    Article  PubMed  Google Scholar 

  6. Cicuttini FM, Wluka AE (2014) Osteoarthritis: is OA a mechanical or systemic disease? Nat Rev Rheumatol. doi:10.1038/nrrheum.2014.114

    PubMed  Google Scholar 

  7. Srikanth VK, Fryer JL, Zhai G, Winzenberg TM, Hosmer D, Jones G (2005) A meta-analysis of sex differences prevalence, incidence and severity of osteoarthritis. Osteoarthr Cartil 13(9):769–781

    Article  PubMed  Google Scholar 

  8. Spector TD, Cicuttini F, Baker J, Loughlin J, Hart D (1996) Genetic influences on osteoarthritis in women: a twin study. BMJ 312(7036):940–943

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. MacGregor AJ, Antoniades L, Matson M, Andrew T, Spector TD (2000) The genetic contribution to radiographic hip osteoarthritis in women: results of a classic twin study. Arthr Rheum 43(11):2410–2416. doi:10.1002/1529-0131(200011)43:11<2410:AID-ANR6>3.0.CO;2-E

    Article  CAS  Google Scholar 

  10. Zhai G, Hart DJ, Kato BS, Macgregor A, Spector TD (2007) Genetic influence on the progression of radiographic knee osteoarthritis: a longitudinal twin study. Osteoarthr Cartil 15(2):222–225

  11. Hindorff LA, Morales J, Junkins HA, Hall PN, Klemm AK, Manolio TA. A catalog of published genome-wide association studies. http://www.genome.gov/gwastudies. Accessed 30 July 2014

  12. Panoutsopoulou K, Zeggini E (2013) Advances in osteoarthritis genetics. J Med Genet 50(11):715–724. doi:10.1136/jmedgenet-2013-101754

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Kerkhof HJ, Bierma-Zeinstra SM, Arden NK, Metrustry S, Castano-Betancourt M, Hart DJ, Hofman A, Rivadeneira F, Oei EH, Spector TD, Uitterlinden AG, Janssens AC, Valdes AM, van Meurs JB (2013) Prediction model for knee osteoarthritis incidence, including clinical, genetic and biochemical risk factors. Ann Rheum Dis. doi:10.1136/annrheumdis-2013-203620

    Google Scholar 

  14. Civelek M, Lusis AJ (2014) Systems genetics approaches to understand complex traits. Nat Rev Genet 15(1):34–48. doi:10.1038/nrg3575

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Assoian RK, Komoriya A, Meyers CA, Miller DM, Sporn MB (1983) Transforming growth factor-β in human platelets. Identification of a major storage site, purification, and characterization. J Biol Chem 258(11):7155–7160

    CAS  PubMed  Google Scholar 

  16. Shi Y, Massague J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113(6):685–700

    Article  CAS  PubMed  Google Scholar 

  17. Massague J, Blain SW, Lo RS (2000) TGFβ signaling in growth control, cancer, and heritable disorders. Cell 103(2):295–309

    Article  CAS  PubMed  Google Scholar 

  18. Hinck AP (2012) Structural studies of the TGF-βs and their receptors—insights into evolution of the TGF-β superfamily. FEBS Lett 586(14):1860–1870. doi:10.1016/j.febslet.2012.05.028

    Article  CAS  PubMed  Google Scholar 

  19. Massague J (2000) How cells read TGF-β signals. Nat Rev Mol Cell Biol 1(3):169–178. doi:10.1038/35043051

    Article  CAS  PubMed  Google Scholar 

  20. Wilkes MC, Murphy SJ, Garamszegi N, Leof EB (2003) Cell-type-specific activation of PAK2 by transforming growth factor beta independent of Smad2 and Smad3. Mol Cell Biol 23(23):8878–8889

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Wilkes MC, Mitchell H, Penheiter SG, Dore JJ, Suzuki K, Edens M, Sharma DK, Pagano RE, Leof EB (2005) Transforming growth factor-β activation of phosphatidylinositol 3-kinase is independent of Smad2 and Smad3 and regulates fibroblast responses via p21-activated kinase-2. Cancer Res 65(22):10431–10440. doi:10.1158/0008-5472.CAN-05-1522

    Article  CAS  PubMed  Google Scholar 

  22. Penheiter SG, Mitchell H, Garamszegi N, Edens M, Dore JJ Jr, Leof EB (2002) Internalization-dependent and -independent requirements for transforming growth factor beta receptor signaling via the Smad pathway. Mol Cell Biol 22(13):4750–4759

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Mehra A, Wrana JL (2002) TGF-beta and the Smad signal transduction pathway. Biochem Cell Biol. Biochimie et biologie cellulaire 80(5):605–622

    Article  CAS  Google Scholar 

  24. Massague J (2012) TGFbeta signalling in context. Nat Rev Mol Cell Biol 13(10):616–630. doi:10.1038/nrm3434

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298(5600):1912–1934. doi:10.1126/science.1075762

    Article  CAS  PubMed  Google Scholar 

  26. Zhang YE (2009) Non-Smad pathways in TGF-β signaling. Cell Res 19(1):128–139. doi:10.1038/cr.2008.328

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Hough C, Radu M, Dore JJ (2012) TGF-beta induced Erk phosphorylation of smad linker region regulates smad signaling. PLoS ONE 7(8):e42513. doi:10.1371/journal.pone.0042513

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Wang W, Rigueur D, Lyons KM (2014) TGFβ signaling in cartilage development and maintenance. Birth Defects Res C Embryo Today 102(1):37–51. doi:10.1002/bdrc.21058

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Pacifici M, Koyama E, Shibukawa Y, Wu C, Tamamura Y, Enomoto-Iwamoto M, Iwamoto M (2006) Cellular and molecular mechanisms of synovial joint and articular cartilage formation. Ann N Y Acad Sci 1068:74–86. doi:10.1196/annals.1346.010

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Buxton P, Edwards C, Archer CW, Francis-West P (2001) Growth/differentiation factor-5 (GDF-5) and skeletal development. J Bone Joint Surg Am 83-A Suppl 1(Pt 1):S23–S30

    CAS  PubMed  Google Scholar 

  31. Thomas JT, Kilpatrick MW, Lin K, Erlacher L, Lembessis P, Costa T, Tsipouras P, Luyten FP (1997) Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1. Nat Genet 17(1):58–64. doi:10.1038/ng0997-58

    Article  CAS  PubMed  Google Scholar 

  32. Seemann P, Schwappacher R, Kjaer KW, Krakow D, Lehmann K, Dawson K, Stricker S, Pohl J, Ploger F, Staub E, Nickel J, Sebald W, Knaus P, Mundlos S (2005) Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2. J Clin Invest 115(9):2373–2381. doi:10.1172/JCI25118

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Baldridge D, Shchelochkov O, Kelley B, Lee B (2010) Signaling pathways in human skeletal dysplasias. Annu Rev Genomics Hum Genet 11:189–217. doi:10.1146/annurev-genom-082908-150158

    Article  CAS  PubMed  Google Scholar 

  34. Iwamoto M, Ohta Y, Larmour C, Enomoto-Iwamoto M (2013) Toward regeneration of articular cartilage. Birth Defects Res C Embryo Today 99(3):192–202. doi:10.1002/bdrc.21042

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Long F, Ornitz DM (2013) Development of the endochondral skeleton. Cold Spring Harb Perspect Biol 5(1):a008334. doi:10.1101/cshperspect.a008334

    Article  PubMed Central  PubMed  Google Scholar 

  36. Bi W, Deng JM, Zhang Z, Behringer RR, de Crombrugghe B (1999) Sox9 is required for cartilage formation. Nat Genet 22(1):85–89. doi:10.1038/8792

    Article  CAS  PubMed  Google Scholar 

  37. Bi W, Huang W, Whitworth DJ, Deng JM, Zhang Z, Behringer RR, de Crombrugghe B (2001) Haploinsufficiency of Sox9 results in defective cartilage primordia and premature skeletal mineralization. Proc Natl Acad Sci USA 98(12):6698–6703. doi:10.1073/pnas.111092198

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Roman-Blas JA, Stokes DG, Jimenez SA (2007) Modulation of TGF-β signaling by proinflammatory cytokines in articular chondrocytes. Osteoarthr Cartil 15(12):1367–1377. doi:10.1016/j.joca.2007.04.011

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Kim YI, Ryu JS, Yeo JE, Choi YJ, Kim YS, Ko K, Koh YG (2014) Overexpression of TGF-β1 enhances chondrogenic differentiation and proliferation of human synovium-derived stem cells. Biochem Biophys Res Commun 450(4):1593–1599. doi:10.1016/j.bbrc.2014.07.045

    Article  CAS  PubMed  Google Scholar 

  40. Furumatsu T, Ozaki T, Asahara H (2009) Smad3 activates the Sox9-dependent transcription on chromatin. Int J Biochem Cell Biol 41(5):1198–1204. doi:10.1016/j.biocel.2008.10.032

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Yoon BS, Ovchinnikov DA, Yoshii I, Mishina Y, Behringer RR, Lyons KM (2005) Bmpr1a and Bmpr1b have overlapping functions and are essential for chondrogenesis in vivo. Proc Natl Acad Sci USA 102(14):5062–5067. doi:10.1073/pnas.0500031102

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Chimal-Monroy J, Rodriguez-Leon J, Montero JA, Ganan Y, Macias D, Merino R, Hurle JM (2003) Analysis of the molecular cascade responsible for mesodermal limb chondrogenesis: sox genes and BMP signaling. Dev Biol 257(2):292–301

    Article  CAS  PubMed  Google Scholar 

  43. Barry F, Boynton RE, Liu B, Murphy JM (2001) Chondrogenic differentiation of mesenchymal stem cells from bone marrow: differentiation-dependent gene expression of matrix components. Exp Cell Res 268(2):189–200. doi:10.1006/excr.2001.5278

    Article  CAS  PubMed  Google Scholar 

  44. Tuli R, Tuli S, Nandi S, Huang X, Manner PA, Hozack WJ, Danielson KG, Hall DJ, Tuan RS (2003) Transforming growth factor-β-mediated chondrogenesis of human mesenchymal progenitor cells involves N-cadherin and mitogen-activated protein kinase and Wnt signaling cross-talk. J Biol Chem 278(42):41227–41236. doi:10.1074/jbc.M305312200

    Article  CAS  PubMed  Google Scholar 

  45. Pelton RW, Saxena B, Jones M, Moses HL, Gold LI (1991) Immunohistochemical localization of TGF beta 1, TGF beta 2, and TGF beta 3 in the mouse embryo: expression patterns suggest multiple roles during embryonic development. J Cell Biol 115(4):1091–1105

    Article  CAS  PubMed  Google Scholar 

  46. Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D et al (1992) Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature 359(6397):693–699. doi:10.1038/359693a0

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Baffi MO, Slattery E, Sohn P, Moses HL, Chytil A, Serra R (2004) Conditional deletion of the TGF-β type II receptor in Col2a expressing cells results in defects in the axial skeleton without alterations in chondrocyte differentiation or embryonic development of long bones. Dev Biol 276(1):124–142. doi:10.1016/j.ydbio.2004.08.027

    Article  CAS  PubMed  Google Scholar 

  48. Matsunobu T, Torigoe K, Ishikawa M, de Vega S, Kulkarni AB, Iwamoto Y, Yamada Y (2009) Critical roles of the TGF-β type I receptor ALK5 in perichondrial formation and function, cartilage integrity, and osteoblast differentiation during growth plate development. Dev Biol 332(2):325–338. doi:10.1016/j.ydbio.2009.06.002

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Zanninelli G, Vetuschi A, Sferra R, D’Angelo A, Fratticci A, Continenza MA, Chiaramonte M, Gaudio E, Caprilli R, Latella G (2006) Smad3 knock-out mice as a useful model to study intestinal fibrogenesis. World J Gastroenterol 12(8):1211–1218

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Zhu Y, Richardson JA, Parada LF, Graff JM (1998) Smad3 mutant mice develop metastatic colorectal cancer. Cell 94(6):703–714

    Article  CAS  PubMed  Google Scholar 

  51. Yang X, Chen L, Xu X, Li C, Huang C, Deng CX (2001) TGF-beta/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. J Cell Biol 153(1):35–46

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Zhang J, Tan X, Li W, Wang Y, Wang J, Cheng X, Yang X (2005) Smad4 is required for the normal organization of the cartilage growth plate. Dev Biol 284(2):311–322. doi:10.1016/j.ydbio.2005.05.036

    Article  CAS  PubMed  Google Scholar 

  53. Retting KN, Song B, Yoon BS, Lyons KM (2009) BMP canonical Smad signaling through Smad1 and Smad5 is required for endochondral bone formation. Development 136(7):1093–1104. doi:10.1242/dev.029926

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Song B, Estrada KD, Lyons KM (2009) Smad signaling in skeletal development and regeneration. Cytokine Growth Factor Rev 20(5–6):379–388. doi:10.1016/j.cytogfr.2009.10.010

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Seo HS, Serra R (2007) Deletion of Tgfbr2 in Prx1-cre expressing mesenchyme results in defects in development of the long bones and joints. Dev Biol 310(2):304–316. doi:10.1016/j.ydbio.2007.07.040

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Tchetina EV, Antoniou J, Tanzer M, Zukor DJ, Poole AR (2006) Transforming growth factor-β2 suppresses collagen cleavage in cultured human osteoarthritic cartilage, reduces expression of genes associated with chondrocyte hypertrophy and degradation, and increases prostaglandin E(2) production. Am J Pathol 168(1):131–140

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Dehne T, Karlsson C, Ringe J, Sittinger M, Lindahl A (2009) Chondrogenic differentiation potential of osteoarthritic chondrocytes and their possible use in matrix-associated autologous chondrocyte transplantation. Arthritis Res Ther 11(5):R133. doi:10.1186/ar2800

    Article  PubMed Central  PubMed  Google Scholar 

  58. Tardif G, Pelletier JP, Fahmi H, Hum D, Zhang Y, Kapoor M, Martel-Pelletier J (2013) NFAT3 and TGF-β/SMAD3 regulate the expression of miR-140 in osteoarthritis. Arthritis Res Ther 15(6):R197. doi:10.1186/ar4387

    Article  PubMed Central  PubMed  Google Scholar 

  59. Tuddenham L, Wheeler G, Ntounia-Fousara S, Waters J, Hajihosseini MK, Clark I, Dalmay T (2006) The cartilage specific microRNA-140 targets histone deacetylase 4 in mouse cells. FEBS Lett 580(17):4214–4217. doi:10.1016/j.febslet.2006.06.080

    Article  CAS  PubMed  Google Scholar 

  60. Massicotte F, Lajeunesse D, Benderdour M, Pelletier JP, Hilal G, Duval N, Martel-Pelletier J (2002) Can altered production of interleukin-1β, interleukin-6, transforming growth factor-β and prostaglandin E(2) by isolated human subchondral osteoblasts identify two subgroups of osteoarthritic patients. Osteoarthr Cartil 10(6):491–500. doi:10.1053/joca.2002.0528

    Article  CAS  PubMed  Google Scholar 

  61. 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. doi:10.1002/1529-0131(199709)40:9<1653:AID-ART15>3.0.CO;2-4

    Article  CAS  PubMed  Google Scholar 

  62. Leivonen SK, Ala-Aho R, Koli K, Grenman R, Peltonen J, Kahari VM (2006) Activation of Smad signaling enhances collagenase-3 (MMP-13) expression and invasion of head and neck squamous carcinoma cells. Oncogene 25(18):2588–2600. doi:10.1038/sj.onc.1209291

    Article  CAS  PubMed  Google Scholar 

  63. Selvamurugan N, Fung Z, Partridge NC (2002) Transcriptional activation of collagenase-3 by transforming growth factor-β1 is via MAPK and Smad pathways in human breast cancer cells. FEBS Lett 532(1–2):31–35

    Article  CAS  PubMed  Google Scholar 

  64. Leivonen SK, Chantry A, Hakkinen L, Han J, Kahari VM (2002) Smad3 mediates transforming growth factor-β-induced collagenase-3 (matrix metalloproteinase-13) expression in human gingival fibroblasts. Evidence for cross-talk between Smad3 and p38 signaling pathways. J Biol Chem 277(48):46338–46346. doi:10.1074/jbc.M206535200

    Article  CAS  PubMed  Google Scholar 

  65. Selvamurugan N, Kwok S, Alliston T, Reiss M, Partridge NC (2004) Transforming growth factor-β1 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 279(18):19327–19334. doi:10.1074/jbc.M314048200

    Article  CAS  PubMed  Google Scholar 

  66. Papathanasiou I, Malizos KN, Tsezou A (2012) Bone morphogenetic protein-2-induced Wnt/beta-catenin signaling pathway activation through enhanced low-density-lipoprotein receptor-related protein 5 catabolic activity contributes to hypertrophy in osteoarthritic chondrocytes. Arthritis Res Ther 14(2):R82. doi:10.1186/ar3805

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Wu Q, Kim KO, Sampson ER, Chen D, Awad H, O’Brien T, Puzas JE, Drissi H, Schwarz EM, O’Keefe RJ, Zuscik MJ, Rosier RN (2008) Induction of an osteoarthritis-like phenotype and degradation of phosphorylated Smad3 by Smurf2 in transgenic mice. Arthritis Rheum 58(10):3132–3144. doi:10.1002/art.23946

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Chen CG, Thuillier D, Chin EN, Alliston T (2012) Chondrocyte-intrinsic Smad3 represses Runx2-inducible matrix metalloproteinase 13 expression to maintain articular cartilage and prevent osteoarthritis. Arthritis Rheum 64(10):3278–3289. doi:10.1002/art.34566

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. van der Kraan PM (2014) Age-related alterations in TGF beta signaling as a causal factor of cartilage degeneration in osteoarthritis. Bio-Med Mater Eng 24(1 Suppl):75–80. doi:10.3233/BME-140976

    Google Scholar 

  70. Scharstuhl A, Glansbeek HL, van Beuningen HM, Vitters EL, van der Kraan PM, van den Berg WB (2002) Inhibition of endogenous TGF-beta during experimental osteoarthritis prevents osteophyte formation and impairs cartilage repair. J Immunol 169(1):507–514

    Article  CAS  PubMed  Google Scholar 

  71. van Beuningen HM, Glansbeek HL, van der Kraan PM, van den Berg WB (2000) Osteoarthritis-like changes in the murine knee joint resulting from intra-articular transforming growth factor-β injections. Osteoarthr Cartil 8(1):25–33. doi:10.1053/joca.1999.0267

    Article  PubMed  Google Scholar 

  72. Bakker AC, van de Loo FA, van Beuningen HM, Sime P, van Lent PL, van der Kraan PM, Richards CD, van den Berg WB (2001) Overexpression of active TGF-beta-1 in the murine knee joint: evidence for synovial-layer-dependent chondro-osteophyte formation. Osteoarthr Cartil 9(2):128–136. doi:10.1053/joca.2000.0368

    Article  CAS  PubMed  Google Scholar 

  73. Zhen G, Wen C, Jia X, Li Y, Crane JL, Mears SC, Askin FB, Frassica FJ, Chang W, Yao J, Carrino JA, Cosgarea A, Artemov D, Chen Q, Zhao Z, Zhou X, Riley L, Sponseller P, Wan M, Lu WW, Cao X (2013) Inhibition of TGF-beta signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. Nat Med 19(6):704–712. doi:10.1038/nm.3143

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  74. Miyamoto Y, Mabuchi A, Shi D, Kubo T, Takatori Y, Saito S, Fujioka M, Sudo A, Uchida A, Yamamoto S, Ozaki K, Takigawa M, Tanaka T, Nakamura Y, Jiang Q, Ikegawa S (2007) A functional polymorphism in the 5′ UTR of GDF5 is associated with susceptibility to osteoarthritis. Nat Genet 39(4):529–533. doi:10.1038/2005

    Article  CAS  PubMed  Google Scholar 

  75. Southam L, Rodriguez-Lopez J, Wilkins JM, Pombo-Suarez M, Snelling S, Gomez-Reino JJ, Chapman K, Gonzalez A, Loughlin J (2007) An SNP in the 5′-UTR of GDF5 is associated with osteoarthritis susceptibility in Europeans and with in vivo differences in allelic expression in articular cartilage. Hum Mol Genet 16(18):2226–2232. doi:10.1093/hmg/ddm174

    Article  CAS  PubMed  Google Scholar 

  76. Reynard LN, Bui C, Canty-Laird EG, Young DA, Loughlin J (2011) Expression of the osteoarthritis-associated gene GDF5 is modulated epigenetically by DNA methylation. Hum Mol Genet 20(17):3450–3460. doi:10.1093/hmg/ddr253

    Article  CAS  PubMed  Google Scholar 

  77. Reynard LN, Bui C, Syddall CM, Loughlin J (2014) CpG methylation regulates allelic expression of GDF5 by modulating binding of SP1 and SP3 repressor proteins to the osteoarthritis susceptibility SNP rs143383. Hum Genet 133(8):1059–1073. doi:10.1007/s00439-014-1447-z

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  78. Aref-Eshghi E, Rahman P, Zhang H, Martin G, Furey A, Green R, Sun G, Zhai G (2014) Attempt to replicate the published osteoarthritis-associated genetic variants in the Newfoundland & Labrador Population. J Orthop Rheumatol 1(3):5

    Google Scholar 

  79. Yamada Y, Okuizumi H, Miyauchi A, Takagi Y, Ikeda K, Harada A (2000) Association of transforming growth factor beta1 genotype with spinal osteophytosis in Japanese women. Arthritis Rheum 43(2):452–460. doi:10.1002/1529-0131(200002)43:2<452:AID-ANR28>3.0.CO;2-C

    Article  CAS  PubMed  Google Scholar 

  80. Lau HH, Ho AY, Luk KD, Kung AW (2004) Transforming growth factor-β1 gene polymorphisms and bone turnover, bone mineral density and fracture risk in southern Chinese women. Calcif Tissue Int 74(6):516–521. doi:10.1007/s00223-004-0163-4

    Article  CAS  PubMed  Google Scholar 

  81. Hinke V, Seck T, Clanget C, Scheidt-Nave C, Ziegler R, Pfeilschifter J (2001) Association of transforming growth factor-β1 (TGFβ1) T29 → C gene polymorphism with bone mineral density (BMD), changes in BMD, and serum concentrations of TGF-beta1 in a population-based sample of postmenopausal german women. Calcif Tissue Int 69(6):315–320

    Article  CAS  PubMed  Google Scholar 

  82. Kinoshita A, Saito T, Tomita H, Makita Y, Yoshida K, Ghadami M, Yamada K, Kondo S, Ikegawa S, Nishimura G, Fukushima Y, Nakagomi T, Saito H, Sugimoto T, Kamegaya M, Hisa K, Murray JC, Taniguchi N, Niikawa N, Yoshiura K (2000) Domain-specific mutations in TGFB1 result in Camurati–Engelmann disease. Nat Genet 26(1):19–20. doi:10.1038/79128

    Article  CAS  PubMed  Google Scholar 

  83. Kizawa H, Kou I, Iida A, Sudo A, Miyamoto Y, Fukuda A, Mabuchi A, Kotani A, Kawakami A, Yamamoto S, Uchida A, Nakamura K, Notoya K, Nakamura Y, Ikegawa S (2005) An aspartic acid repeat polymorphism in asporin inhibits chondrogenesis and increases susceptibility to osteoarthritis. Nat Genet 37(2):138–144. doi:10.1038/ng1496

    Article  CAS  PubMed  Google Scholar 

  84. Jiang Q, Shi D, Yi L, Ikegawa S, Wang Y, Nakamura T, Qiao D, Liu C, Dai J (2006) Replication of the association of the aspartic acid repeat polymorphism in the asporin gene with knee-osteoarthritis susceptibility in Han Chinese. J Hum Genet 51(12):1068–1072. doi:10.1007/s10038-006-0065-6

    Article  CAS  PubMed  Google Scholar 

  85. Mustafa Z, Dowling B, Chapman K, Sinsheimer JS, Carr A, Loughlin J (2005) Investigating the aspartic acid (D) repeat of asporin as a risk factor for osteoarthritis in a UK Caucasian population. Arthritis Rheum 52(11):3502–3506. doi:10.1002/art.21399

    Article  CAS  PubMed  Google Scholar 

  86. Song YQ, Cheung KM, Ho DW, Poon SC, Chiba K, Kawaguchi Y, Hirose Y, Alini M, Grad S, Yee AF, Leong JC, Luk KD, Yip SP, Karppinen J, Cheah KS, Sham P, Ikegawa S, Chan D (2008) Association of the asporin D14 allele with lumbar-disc degeneration in Asians. Am J Hum Genet 82(3):744–747. doi:10.1016/j.ajhg.2007.12.017

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  87. Wu J, Liu W, Bemis A, Wang E, Qiu Y, Morris EA, Flannery CR, Yang Z (2007) Comparative proteomic characterization of articular cartilage tissue from normal donors and patients with osteoarthritis. Arthritis Rheum 56(11):3675–3684. doi:10.1002/art.22876

    Article  CAS  PubMed  Google Scholar 

  88. Verdier MP, Seite S, Guntzer K, Pujol JP, Boumediene K (2005) Immunohistochemical analysis of transforming growth factor beta isoforms and their receptors in human cartilage from normal and osteoarthritic femoral heads. Rheumatol Int 25(2):118–124. doi:10.1007/s00296-003-0409-x

    Article  CAS  PubMed  Google Scholar 

  89. Blaney Davidson EN, Remst DF, Vitters EL, van Beuningen HM, Blom AB, Goumans MJ, van den Berg WB, van der Kraan PM (2009) Increase in ALK1/ALK5 ratio as a cause for elevated MMP-13 expression in osteoarthritis in humans and mice. J Immunol 182(12):7937–7945. doi:10.4049/jimmunol.0803991

    Article  CAS  PubMed  Google Scholar 

  90. van de Laar IM, Oldenburg RA, Pals G, Roos-Hesselink JW, de Graaf BM, Verhagen JM, Hoedemaekers YM, Willemsen R, Severijnen LA, Venselaar H, Vriend G, Pattynama PM, Collee M, Majoor-Krakauer D, Poldermans D, Frohn-Mulder IM, Micha D, Timmermans J, Hilhorst-Hofstee Y, Bierma-Zeinstra SM, Willems PJ, Kros JM, Oei EH, Oostra BA, Wessels MW, Bertoli-Avella AM (2011) Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet 43(2):121–126. doi:10.1038/ng.744

    Article  PubMed  Google Scholar 

  91. van de Laar IM, van der Linde D, Oei EH, Bos PK, Bessems JH, Bierma-Zeinstra SM, van Meer BL, Pals G, Oldenburg RA, Bekkers JA, Moelker A, de Graaf BM, Matyas G, Frohn-Mulder IM, Timmermans J, Hilhorst-Hofstee Y, Cobben JM, Bruggenwirth HT, van Laer L, Loeys B, De Backer J, Coucke PJ, Dietz HC, Willems PJ, Oostra BA, De Paepe A, Roos-Hesselink JW, Bertoli-Avella AM, Wessels MW (2012) Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome. J Med Genet 49(1):47–57. doi:10.1136/jmedgenet-2011-100382

    Article  PubMed  Google Scholar 

  92. Wischmeijer A, Van Laer L, Tortora G, Bolar NA, Van Camp G, Fransen E, Peeters N, di Bartolomeo R, Pacini D, Gargiulo G, Turci S, Bonvicini M, Mariucci E, Lovato L, Brusori S, Ritelli M, Colombi M, Garavelli L, Seri M, Loeys BL (2013) Thoracic aortic aneurysm in infancy in aneurysms-osteoarthritis syndrome due to a novel SMAD3 mutation: further delineation of the phenotype. Am J Med Genet A 161A(5):1028–1035. doi:10.1002/ajmg.a.35852

    Article  PubMed  Google Scholar 

  93. Regalado ES, Guo DC, Villamizar C, Avidan N, Gilchrist D, McGillivray B, Clarke L, Bernier F, Santos-Cortez RL, Leal SM, Bertoli-Avella AM, Shendure J, Rieder MJ, Nickerson DA, Project NGES, Milewicz DM (2011) Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms. Circ Res 109(6):680–686. doi:10.1161/CIRCRESAHA.111.248161

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  94. Valdes AM, Spector TD, Tamm A, Kisand K, Doherty SA, Dennison EM, Mangino M, Tamm A, Kerna I, Hart DJ, Wheeler M, Cooper C, Lories RJ, Arden NK, Doherty M (2010) Genetic variation in the SMAD3 gene is associated with hip and knee osteoarthritis. Arthritis Rheum 62(8):2347–2352. doi:10.1002/art.27530

    Article  CAS  PubMed  Google Scholar 

  95. Aref-Eshghi E, Zhang Y, Hart D, Valdes AM, Furey A, Martin G, Sun G, Rahman P, Arden N, Spector TD, Zhai G (2014) SMAD3 is associated with the total burden of radiographic osteoarthritis: the Chingford study. PLoS ONE 9(5):e97786. doi:10.1371/journal.pone.0097786

    Article  PubMed Central  PubMed  Google Scholar 

  96. Walker LC, Fredericksen ZS, Wang X, Tarrell R, Pankratz VS, Lindor NM, Beesley J, Healey S, Chen X, kConFab, Stoppa-Lyonnet D, Tirapo C, Giraud S, Mazoyer S, Muller D, Fricker JP, Delnatte C, Collaborators GS, Schmutzler RK, Wappenschmidt B, Engel C, Schonbuchner I, Deissler H, Meindl A, Hogervorst FB, Verheus M, Hooning MJ, van den Ouweland AM, Nelen MR, Ausems MG, Aalfs CM, van Asperen CJ, Devilee P, Gerrits MM, Waisfisz Q, Hebon, Szabo CI, ModSquaD, Easton DF, Peock S, Cook M, Oliver CT, Frost D, Harrington P, Evans DG, Lalloo F, Eeles R, Izatt L, Chu C, Davidson R, Eccles D, Ong KR, Cook J, Embrace, Rebbeck T, Nathanson KL, Domchek SM, Singer CF, Gschwantler-Kaulich D, Dressler AC, Pfeiler G, Godwin AK, Heikkinen T, Nevanlinna H, Agnarsson BA, Caligo MA, Olsson H, Kristoffersson U, Liljegren A, Arver B, Karlsson P, Melin B, Swe B, Sinilnikova OM, McGuffog L, Antoniou AC, Chenevix-Trench G, Spurdle AB, Couch FJ (2010) Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers. Breast Cancer Res 12(6):R102. doi:10.1186/bcr2785

  97. Pombo-Suarez M, Castano-Oreja MT, Calaza M, Gomez-Reino J, Gonzalez A (2009) Differential upregulation of the three transforming growth factor beta isoforms in human osteoarthritic cartilage. Ann Rheum Dis 68(4):568–571. doi:10.1136/ard.2008.090217

    Article  CAS  PubMed  Google Scholar 

  98. Finnson KW, Chi Y, Bou-Gharios G, Leask A, Philip A (2012) TGF-b signaling in cartilage homeostasis and osteoarthritis. Front Biosci (Schol Ed) 4:251–268

    Article  Google Scholar 

Download references

Acknowledgments

The study was financially supported by Canadian Institutes of Health Research, Research and Development Corporation of Newfoundland and Labrador Province, Memorial University of Newfoundland.

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Canada

    Guangju Zhai, Jules Doré & Proton Rahman

Authors
  1. Guangju Zhai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jules Doré
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Proton Rahman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guangju Zhai.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhai, G., Doré, J. & Rahman, P. TGF-β signal transduction pathways and osteoarthritis. Rheumatol Int 35, 1283–1292 (2015). https://doi.org/10.1007/s00296-015-3251-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00296-015-3251-z

Keywords

Search

Navigation