TGF-β signal transduction pathways and osteoarthritis

Rheumatology International

Volumn 35, Issue 8, 2015, Pages 1283-1292

  Zhai, Guangju ^a   Doré, Jules ^a   Rahman, Proton ^a  

^a MEMORIAL UNIVERSITY OF NEWFOUNDLAND   (Canada)

Author keywords

BMP; Osteoarthritis; SMAD; TGF signalling pathways

Indexed keywords

BONE MORPHOGENETIC PROTEIN; SMAD PROTEIN; TRANSFORMING GROWTH FACTOR BETA;

ARTICULAR CARTILAGE; CARTILAGE CELL; CHONDROGENESIS; HOMEOSTASIS; HUMAN; IN VITRO STUDY; NONHUMAN; OSTEOARTHRITIS; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; BONE; METABOLISM; OSTEOBLAST;

BONE AND BONES; BONE MORPHOGENETIC PROTEINS; CARTILAGE, ARTICULAR; CHONDROCYTES; HUMANS; OSTEOARTHRITIS; OSTEOBLASTS; SIGNAL TRANSDUCTION; SMAD PROTEINS; TRANSFORMING GROWTH FACTOR BETA;

EID: 84931569939     PISSN: 01728172     EISSN: 1437160X     Source Type: Journal    
DOI: 10.1007/s00296-015-3251-z     Document Type: Review

References (98)

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
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
4. Bitton R (2009) The economic burden of osteoarthritis. Am J Manag Care 15(8 Suppl):S230–S235
5. Felson DT (2004) An update on the pathogenesis and epidemiology of osteoarthritis. Radiol Clin N Am 42(1):1–9
6. Cicuttini FM, Wluka AE (2014) Osteoarthritis: is OA a mechanical or systemic disease? Nat Rev Rheumatol. doi:10.1038/nrrheum.2014.114
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
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
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
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
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
14. Civelek M, Lusis AJ (2014) Systems genetics approaches to understand complex traits. Nat Rev Genet 15(1):34–48. doi:10.1038/nrg3575
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
16. Shi Y, Massague J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113(6):685–700
17. Massague J, Blain SW, Lo RS (2000) TGFβ signaling in growth control, cancer, and heritable disorders. Cell 103(2):295–309
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
19. Massague J (2000) How cells read TGF-β signals. Nat Rev Mol Cell Biol 1(3):169–178. doi:10.1038/35043051
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
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
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
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
24. Massague J (2012) TGFbeta signalling in context. Nat Rev Mol Cell Biol 13(10):616–630. doi:10.1038/nrm3434
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
26. Zhang YE (2009) Non-Smad pathways in TGF-β signaling. Cell Res 19(1):128–139. doi:10.1038/cr.2008.328
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
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
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
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
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
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
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
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
35. Long F, Ornitz DM (2013) Development of the endochondral skeleton. Cold Spring Harb Perspect Biol 5(1):a008334. doi:10.1101/cshperspect.a008334
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
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
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
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
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
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
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
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
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
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
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
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
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
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
50. Zhu Y, Richardson JA, Parada LF, Graff JM (1998) Smad3 mutant mice develop metastatic colorectal cancer. Cell 94(6):703–714
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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