Top

Published in:

01-02-2010 | Review

A role for age-related changes in TGFβ signaling in aberrant chondrocyte differentiation and osteoarthritis

Authors: Peter M van der Kraan, Esmeralda N Blaney Davidson, Wim B van den Berg

Published in: Arthritis Research & Therapy | Issue 1/2010

Abstract

Transforming growth factor beta (TGFβ) is a growth factor with many faces. In our osteoarthritis (OA) research we have found that TGFβ can be protective as well as deleterious for articular cartilage. We postulate that the dual effects of TGFβ on chondrocytes can be explained by the fact that TGFβ can signal via different receptors and related Smad signaling routes. On chondrocytes, TGFβ not only signals via the canonical type I receptor ALK5 but also via the ALK1 receptor. Notably, signaling via ALK5 (Smad2/3 route) results in markedly different chondrocyte responses than ALK1 signaling (Smad1/5/8), and we postulate that the balance between ALK5 and ALK1 expression on chondrocytes will determine the overall effect of TGFβ on these cells. Importantly, signaling via ALK1, but not ALK5, stimulates MMP-13 expression by chondrocytes. In cartilage of ageing mice and in experimental OA models we have found that the ALK1/ALK5 ratio is significantly increased, favoring TGFβ signaling via the Smad1/5/8 route, changes in chondrocyte differentiation and MMP-13 expression. Moreover, human OA cartilage showed a significant correlation between ALK1 and MMP-13 expression. In this paper we summarize concepts in OA, its link with ageing and disturbed growth factor responses, and a potential role of TGFβ signaling in OA development.

Available only for authorised users

Pullig O, Weseloh G, Ronneberger D, Kakonen S, Swoboda B: Chondrocyte differentiation in human osteoarthritis: expression of osteocalcin in normal and osteoarthritic cartilage and bone. Calcif Tissue Int. 2000, 67: 230-240. 10.1007/s002230001108.PubMed

Kirsch T, Swoboda B, Nah H: Activation of annexin II and V expression, terminal differentiation, mineralization and apoptosis in human osteoarthritic cartilage. Osteoarthritis Cartilage. 2000, 8: 294-302. 10.1053/joca.1999.0304.PubMed

Aigner T, Reichenberger E, Bertling W, Kirsch T, Stoss H, von der MK: Type X collagen expression in osteoarthritic and rheumatoid articular cartilage. Virchows Arch B Cell Pathol Incl Mol Pathol. 1993, 63: 205-211. 10.1007/BF02899263.PubMed

Li T, Xiao J, Wu Z, Qiu G: Over-expression of c-maf by chondrocytes in osteoarthritis. J Int Med Res. 2009, 37: 129-135.PubMed

Wang X, Manner PA, Horner A, Shum L, Tuan RS, Nuckolls GH: Regulation of MMP-13 expression by RUNX2 and FGF2 in osteoarthritic cartilage. Osteoarthritis Cartilage. 2004, 12: 963-973. 10.1016/j.joca.2004.08.008.PubMed

Reboul P, Pelletier JP, Tardif G, Cloutier JM, Martel-Pelletier J: The new collagenase, collagenase-3, is expressed and synthesized by human chondrocytes but not by synoviocytes. A role in osteoarthritis. J Clin Invest. 1996, 97: 2011-2019. 10.1172/JCI118636.PubMedCentralPubMed

Inada M, Wang Y, Byrne MH, Rahman MU, Miyaura C, Lopez-Otin C, Krane SM: Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification. Proc Natl Acad Sci USA. 2004, 101: 17192-17197. 10.1073/pnas.0407788101.PubMedCentralPubMed

Stickens D, Behonick DJ, Ortega N, Heyer B, Hartenstein B, Yu Y, Fosang AJ, Schorpp-Kistner M, Angel P, Werb Z: Altered endochondral bone development in matrix metalloproteinase 13-deficient mice. Development. 2004, 131: 5883-5895. 10.1242/dev.01461.PubMedCentralPubMed

Fraser A, Fearon U, Billinghurst RC, Ionescu M, Reece R, Barwick T, Emery P, Poole AR, Veale DJ: Turnover of type II collagen and aggrecan in cartilage matrix at the onset of inflammatory arthritis in humans: relationship to mediators of systemic and local inflammation. Arthritis Rheum. 2003, 48: 3085-3095. 10.1002/art.11331.PubMed

10.

Poole AR, Rizkalla G, Ionescu M, Reiner A, Brooks E, Rorabeck C, Bourne R, Bogoch E: Osteoarthritis in the human knee: a dynamic process of cartilage matrix degradation, synthesis and reorganization. Agents Actions Suppl. 1993, 39: 3-13. 10.1007/BF01972702.PubMed

11.

Hermansson M, Sawaji Y, Bolton M, Alexander S, Wallace A, Begum S, Wait R, Saklatvala J: Proteomic analysis of articular cartilage shows increased type II collagen synthesis in osteoarthritis and expression of inhibin betaA (activin A), a regulatory molecule for chondrocytes. J Biol Chem. 2004, 279: 43514-43521. 10.1074/jbc.M407041200.PubMed

12.

Aigner T, Zien A, Gehrsitz A, Gebhard PM, McKenna L: Anabolic and catabolic gene expression pattern analysis in normal versus osteoarthritic cartilage using complementary DNA-array technology. Arthritis Rheum. 2001, 44: 2777-2789. 10.1002/1529-0131(200112)44:12<2777::AID-ART465>3.0.CO;2-H.PubMed

13.

Martel-Pelletier J, McCollum R, DiBattista J, Faure MP, Chin JA, Fournier S, Sarfati M, Pelletier JP: The interleukin-1 receptor in normal and osteoarthritic human articular chondrocytes. Identification as the type I receptor and analysis of binding kinetics and biologic function. Arthritis Rheum. 1992, 35: 530-540. 10.1002/art.1780350507.PubMed

14.

Shlopov BV, Gumanovskaya ML, Hasty KA: Autocrine regulation of collagenase 3 (matrix metalloproteinase 13) during osteoarthritis. Arthritis Rheum. 2000, 43: 195-205. 10.1002/1529-0131(200001)43:1<195::AID-ANR24>3.0.CO;2-G.PubMed

15.

Dingle JT: Catabolin - a cartilage catabolic factor from synovium. Clin Orthop Relat Res. 1981, 156: 219-231.PubMed

16.

Martel-Pelletier J: Pathophysiology of osteoarthritis. Osteoarthritis Cartilage. 2004, 12 (Suppl A): S31-S33. 10.1016/j.joca.2003.10.002.PubMed

17.

Vuolteenaho K, Moilanen T, Jalonen U, Lahti A, Nieminen R, van Beuningen HM, Kraan van der PM, Moilanen E: TGFβ inhibits IL-1-induced iNOS expression and NO production in immortalized chondrocytes. Inflamm Res. 2005, 54: 420-427. 10.1007/s00011-005-1373-6.PubMed

18.

Pasternak RD, Hubbs SJ, Caccese RG, Marks RL, Conaty JM, DiPasquale G: Interleukin-1 stimulates the secretion of proteoglycan- and collagendegrading proteases by rabbit articular chondrocytes. Clin Immunol Immunopathol. 1986, 41: 351-367. 10.1016/0090-1229(86)90006-1.PubMed

19.

Takahashi N, Rieneck K, Kraan van der PM, van Beuningen HM, Vitters EL, Bendtzen K, Berg van den WB: Elucidation of IL-1/TGF-β interactions in mouse chondrocyte cell line by genome-wide gene expression. Osteoarthritis Cartilage. 2005, 13: 426-438. 10.1016/j.joca.2004.12.010.PubMed

20.

Bocquet J, Daireaux M, Langris M, Jouis V, Pujol JP, Beliard R, Loyau G: Effect of a interleukin-1 like factor (mononuclear cell factor) on proteoglycan synthesis in cultured human articular chondrocytes. Biochem Biophys Res Commun. 1986, 134: 539-549. 10.1016/S0006-291X(86)80454-5.PubMed

21.

Goldring MB, Birkhead JR, Suen LF, Yamin R, Mizuno S, Glowacki J, Arbiser JL, Apperley JF: Interleukin-1 beta-modulated gene expression in immortalized human chondrocytes. J Clin Invest. 1994, 94: 2307-2316. 10.1172/JCI117595.PubMedCentralPubMed

22.

Bhatnagar R, Penfornis H, Mauviel A, Loyau G, Saklatvala J, Pujol JP: Interleukin-1 inhibits the synthesis of collagen by fibroblasts. Biochem Int. 1986, 13: 709-720.PubMed

23.

Redini F, Galera P, Mauviel A, Loyau G, Pujol JP: Transforming growth factor beta stimulates collagen and glycosaminoglycan biosynthesis in cultured rabbit articular chondrocytes. FEBS Lett. 1988, 234: 172-176. 10.1016/0014-5793(88)81327-9.PubMed

24.

Redini F, Daireaux M, Mauviel A, Galera P, Loyau G, Pujol JP: Characterization of proteoglycans synthesized by rabbit articular chondrocytes in response to transforming growth factor-beta (TGF-β). Biochim Biophys Acta. 1991, 1093: 196-206. 10.1016/0167-4889(91)90123-F.PubMed

25.

Goldring MB: The role of cytokines as inflammatory mediators in osteoarthritis: lessons from animal models. Connect Tissue Res. 1999, 40: 1-11. 10.3109/03008209909005273.PubMed

26.

Kraan van der PM, Glansbeek HL, Vitters EL, Berg van den WB: Early elevation of transforming growth factor-beta, decorin, and biglycan mRNA levels during cartilage matrix restoration after mild proteoglycan depletion. J Rheumatol. 1997, 24: 543-549.PubMed

27.

Govinden R, Bhoola KD: Genealogy, expression, and cellular function of transforming growth factor-beta. Pharmacol Ther. 2003, 98: 257-265. 10.1016/S0163-7258(03)00035-4.PubMed

28.

Lawrence DA: Latent-TGF-β: an overview. Mol Cell Biochem. 2001, 219: 163-170. 10.1023/A:1010819716023.PubMed

29.

Konig HG, Kogel D, Rami A, Prehn JH: TGFβ₁ activates two distinct type I receptors in neurons: implications for neuronal NF-κB signaling. J Cell Biol. 2005, 168: 1077-1086. 10.1083/jcb.200407027.PubMedCentralPubMed

30.

Finnson KW, Parker WL, ten DP, Thorikay M, Philip A: ALK1 opposes ALK5/Smad3 signaling and expression of extracellular matrix components in human chondrocytes. J Bone Miner Res. 2008, 23: 896-906. 10.1359/jbmr.080209.PubMed

31.

Goumans MJ, Valdimarsdottir G, Itoh S, Lebrin F, Larsson J, Mummery C, Karlsson S, ten Dijke P: Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFbeta/ALK5 signaling. Mol Cell. 2003, 12: 817-828. 10.1016/S1097-2765(03)00386-1.PubMed

32.

Wu X, Ma J, Han JD, Wang N, Chen YG: Distinct regulation of gene expression in human endothelial cells by TGF-β and its receptors. Microvasc Res. 2006, 71: 12-19. 10.1016/j.mvr.2005.11.004.PubMed

33.

Seki T, Hong KH, Oh SP: Nonoverlapping expression patterns of ALK1 and ALK5 reveal distinct roles of each receptor in vascular development. Lab Invest. 2006, 86: 116-129. 10.1038/labinvest.3700376.PubMed

34.

Goumans MJ, Valdimarsdottir G, Itoh S, Rosendahl A, Sideras P, ten Dijke P: Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. EMBO J. 2002, 21: 1743-1753. 10.1093/emboj/21.7.1743.PubMedCentralPubMed

35.

Zhang YE: Non-Smad pathways in TGF-β signaling. Cell Res. 2009, 19: 128-139. 10.1038/cr.2008.328.PubMedCentralPubMed

36.

Sorrentino A, Thakur N, Grimsby S, Marcusson A, von BV, Schuster N, Zhang S, Heldin CH, Landstrom M: The type I TGF-β receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. Nat Cell Biol. 2008, 10: 1199-1207. 10.1038/ncb1780.PubMed

37.

Kamiya M, Harada A, Mizuno M, Iwata H, Yamada Y: Association between a polymorphism of the transforming growth factor-β₁ gene and genetic susceptibility to ossification of the posterior longitudinal ligament in Japanese patients. Spine. 2001, 26: 1264-1266. 10.1097/00007632-200106010-00017.PubMed

38.

Yamada Y, Okuizumi H, Miyauchi A, Takagi Y, Ikeda K, Harada A: Association of transforming growth factor beta 1 genotype with spinal osteophytosis in Japanese women. Arthritis Rheum. 2000, 43: 452-460. 10.1002/1529-0131(200002)43:2<452::AID-ANR28>3.0.CO;2-C.PubMed

39.

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: An aspartic acid repeat polymorphism in asporin inhibits chondrogenesis and increases susceptibility to osteoarthritis. Nat Genet. 2005, 37: 138-144. 10.1038/ng1496.PubMed

40.

Rodriguez-Lopez J, Pombo-Suarez M, Liz M, Gomez-Reino JJ, Gonzalez A: Lack of association of a variable number of aspartic acid residues in the asporin gene with osteoarthritis susceptibility: case-control studies in Spanish Caucasians. Arthritis Res Ther. 2006, 8: R55-10.1186/ar1920.PubMedCentralPubMed

41.

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

42.

Serra R, Johnson M, Filvaroff EH, Laborde J, Sheehan DM, Derynck R, Moses HL: Expression of a truncated, kinase defective TGF-beta type II receptor in mouse skeletal tissue promotes terminal chondrocyte differentiation and osteoarthritis. J Cell Biol. 1997, 139: 541-552. 10.1083/jcb.139.2.541.PubMedCentralPubMed

43.

Yang X, Chen L, Xu XL, Li CL, Huang CF, Deng CX: TGF-β/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. J Cell Biol. 2001, 153: 35-46. 10.1083/jcb.153.1.35.PubMedCentralPubMed

44.

Dabovic B, Chen Y, Colarossi C, Zambuto L, Obata H, Rifkin DB: Bone defects in latent TGF-β binding protein (Ltbp)-3 null mice, a role for Ltbp in TGF- β presentation. J Endocrinol. 2002, 175: 129-141. 10.1677/joe.0.1750129.PubMed

45.

Vivien D, Galera P, Loyau G, Pujol JP: Differential response of cultured rabbit articular chondrocytes (RAC) to transforming growth factor beta (TGF-β) - evidence for a role of serum factors. Eur J Cell Biol. 1991, 54: 217-223.PubMed

46.

Vivien D, Galera P, Lebrun E, Daireaux M, Loyau G, Pujol JP: TGF-β-induced G2/M delay in proliferating rabbit articular chondrocytes is associated with an enhancement of replication rate and a cAMP decrease: possible involvement of pertussis toxin-sensitive pathway. J Cell Physiol. 1992, 150: 291-298. 10.1002/jcp.1041500211.PubMed

47.

Vivien D, Redini F, Galera P, Lebrun E, Loyau G, Pujol JP: Rabbit articular chondrocytes (RAC) express distinct transforming growth factor-beta receptor phenotypes as a function of cell cycle phases. Exp Cell Res. 1993, 205: 165-170. 10.1006/excr.1993.1071.PubMed

48.

Pujol JP, Galera P, Pronost S, Boumediene K, Vivien D, Macro M, Min W, Redini F, Penfornis H, Daireaux M: Transforming growth factor-beta (TGF-β) and articular chondrocytes. Ann Endocrinol (Paris). 1994, 55: 109-120.

49.

Boumediene K, Felisaz N, Pujol JP: Cell-cycle-dependent expression of transforming growth factor beta type I receptor correlates with differential proliferative effects of TGFβ₁ in articular chondrocytes. Exp Cell Res. 1998, 243: 173-184. 10.1006/excr.1998.4129.PubMed

50.

Pujol JP, Chadjichristos C, Legendre F, Bauge C, Beauchef G, Andriamanalijaona R, Galera P, Boumediene K: Interleukin-1 and transforming growth factor-beta 1 as crucial factors in osteoarthritic cartilage metabolism. Connect Tissue Res. 2008, 49: 293-297. 10.1080/03008200802148355.PubMed

51.

Legendre F, Dudhia J, Pujol JP, Bogdanowicz P: JAK/STAT but not ERK1/ERK2 pathway mediates interleukin (IL)-6/soluble IL-6R down-regulation of type II collagen, aggrecan core, and link protein transcription in articular chondrocytes. Association with a down-regulation of SOX9 expression. J Biol Chem. 2003, 278: 2903-2912. 10.1074/jbc.M110773200.PubMed

52.

Blaney Davidson EN, Scharstuhl A, Vitters EL, Kraan van der PM, Berg van den WB: Reduced transforming growth factor-beta signaling in cartilage of old mice: role in impaired repair capacity. Arthritis Res Ther. 2005, 7: R1338-R1347. 10.1186/ar1833.PubMedCentralPubMed

53.

Scharstuhl A, van Beuningen HM, Vitters EL, Kraan van der PM, Berg van den WB: Loss of transforming growth factor counteraction on interleukin 1 mediated effects in cartilage of old mice. Ann Rheum Dis. 2002, 61: 1095-1098. 10.1136/ard.61.12.1095.PubMedCentralPubMed

54.

Galera P, Redini F, Vivien D, Bonaventure J, Penfornis H, Loyau G, Pujol JP: Effect of transforming growth factor-beta 1 (TGF-β1) on matrix synthesis by monolayer cultures of rabbit articular chondrocytes during the dedifferentiation process. Exp Cell Res. 1992, 200: 379-392. 10.1016/0014-4827(92)90186-C.PubMed

55.

Kraan van der PM, Vitters E, van den BW: Differential effect of transforming growth factor beta on freshly isolated and cultured articular chondrocytes. J Rheumatol. 1992, 19: 140-145.PubMed

56.

Morales TI: Transforming growth factor-beta 1 stimulates synthesis of proteoglycan aggregates in calf articular cartilage organ cultures. Arch Biochem Biophys. 1991, 286: 99-106. 10.1016/0003-9861(91)90013-9.PubMed

57.

Morales TI, Roberts AB: Transforming growth factor beta regulates the metabolism of proteoglycans in bovine cartilage organ cultures. J Biol Chem. 1988, 263: 12828-12831.PubMed

58.

van Beuningen HM, Kraan van der PM, Arntz OJ, Berg van den WB: Transforming growth factor-beta 1 stimulates articular chondrocyte proteoglycan synthesis and induces osteophyte formation in the murine knee joint. Lab Invest. 1994, 71: 279-290.PubMed

59.

60.

Livne E, Laufer D, Blumenfeld I: Differential response of articular cartilage from young growing and mature old mice to IL-1 and TGF-β. Arch Gerontol Geriatr. 1997, 24: 211-221. 10.1016/S0167-4943(96)00753-4.PubMed

61.

McCaffrey TA, Falcone DJ: Evidence for an age-related dysfunction in the antiproliferative response to transforming growth factor-beta in vascular smooth muscle cells. Mol Biol Cell. 1993, 4: 315-322.PubMedCentralPubMed

62.

Mailhot G, Yang M, Mason-Savas A, Mackay CA, Leav I, Odgren PR: BMP-5 expression increases during chondrocyte differentiation in vivo and in vitro and promotes proliferation and cartilage matrix synthesis in primary chondrocyte cultures. J Cell Physiol. 2008, 214: 56-64. 10.1002/jcp.21164.PubMedCentralPubMed

63.

Li X, Schwarz EM, Zuscik MJ, Rosier RN, Ionescu AM, Puzas JE, Drissi H, Sheu TJ, O'keefe RJ: Retinoic acid stimulates chondrocyte differentiation and enhances bone morphogenetic protein effects through induction of Smad1 and Smad5. Endocrinology. 2003, 144: 2514-2523. 10.1210/en.2002-220969.PubMed

64.

Nishihara A, Fujii M, Sampath TK, Miyazono K, Reddi AH: Bone morphogenetic protein signaling in articular chondrocyte differentiation. Biochem Biophys Res Commun. 2003, 301: 617-622. 10.1016/S0006-291X(02)03068-1.PubMed

65.

Bau B, Haag J, Schmid E, Kaiser M, Gebhard PM, Aigner T: Bone morphogenetic protein-mediating receptor-associated Smads as well as common Smad are expressed in human articular chondrocytes but not up-regulated or down-regulated in osteoarthritic cartilage. J Bone Miner Res. 2002, 17: 2141-2150. 10.1359/jbmr.2002.17.12.2141.PubMed

66.

Drissi MH, Li X, Sheu TJ, Zuscik MJ, Schwarz EM, Puzas JE, Rosier RN, O'keefe RJ: Runx2/Cbfa1 stimulation by retinoic acid is potentiated by BMP2 signaling through interaction with Smad1 on the collagen X promoter in chondrocytes. J Cell Biochem. 2003, 90: 1287-1298. 10.1002/jcb.10677.PubMed

67.

Li X, Ionescu AM, Schwarz EM, Zhang X, Drissi H, Puzas JE, Rosier RN, Zuscik MJ, O'keefe RJ: Smad6 is induced by BMP-2 and modulates chondrocyte differentiation. J Orthop Res. 2003, 21: 908-913. 10.1016/S0736-0266(03)00008-1.PubMed

68.

Horiki M, Imamura T, Okamoto M, Hayashi M, Murai J, Myoui A, Ochi T, Miyazono K, Yoshikawa H, Tsumaki N: Smad6/Smurf1 overexpression in cartilage delays chondrocyte hypertrophy and causes dwarfism with osteopenia. J Cell Biol. 2004, 165: 433-445. 10.1083/jcb.200311015.PubMedCentralPubMed

69.

Zuscik MJ, Baden JF, Wu Q, Sheu TJ, Schwarz EM, Drissi H, O'keefe RJ, Puzas JE, Rosier RN: 5-Azacytidine alters TGF-β and BMP signaling and induces maturation in articular chondrocytes. J Cell Biochem. 2004, 92: 316-331. 10.1002/jcb.20050.PubMed

70.

Li TF, Darowish M, Zuscik MJ, Chen D, Schwarz EM, Rosier RN, Drissi H, O'Keefe RJ: Smad3-deficient chondrocytes have enhanced BMP signaling and accelerated differentiation. J Bone Miner Res. 2006, 21: 4-16. 10.1359/JBMR.050911.PubMedCentralPubMed

71.

Yang X, Chen L, Xu X, Li C, Huang C, Deng CX: TGF-β/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. J Cell Biol. 2001, 153: 35-46. 10.1083/jcb.153.1.35.PubMedCentralPubMed

72.

Ferguson CM, Schwarz EM, Reynolds PR, Puzas JE, Rosier RN, O'keefe RJ: Smad2 and 3 mediate transforming growth factor-beta1-induced inhibition of chondrocyte maturation. Endocrinology. 2000, 141: 4728-4735. 10.1210/en.141.12.4728.PubMed

73.

Zhou S, Eid K, Glowacki J: Cooperation between TGF-β and Wnt pathways during chondrocyte and adipocyte differentiation of human marrow stromal cells. J Bone Miner Res. 2004, 19: 463-470. 10.1359/JBMR.0301239.PubMed

74.

Zhu M, Tang D, Wu Q, Hao S, Chen M, Xie C, Rosier RN, O'Keefe RJ, Zuscik M, Chen D: Activation of β-catenin signaling in articular chondrocytes leads to osteoarthritis-like phenotype in adult beta-catenin conditional activation mice. J Bone Miner Res. 2009, 24: 12-21. 10.1359/jbmr.080901.PubMedCentralPubMed

75.

Zhu M, Chen M, Zuscik M, Wu Q, Wang YJ, Rosier RN, O'Keefe RJ, Chen D: Inhibition of β-catenin signaling in articular chondrocytes results in articular cartilage destruction. Arthritis Rheum. 2008, 58: 2053-2064. 10.1002/art.23614.PubMedCentralPubMed

76.

Weng LH, Wang CJ, Ko JY, Sun YC, Su YS, Wang FS: Inflammation induction of Dickkopf-1 mediates chondrocyte apoptosis in osteoarthritic joint. Osteoarthritis Cartilage. 2009, 17: 933-943. 10.1016/j.joca.2008.12.008.PubMed

77.

Fuentealba LC, Eivers E, Ikeda A, Hurtado C, Kuroda H, Pera EM, De Robertis EM: Integrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signal. Cell. 2007, 131: 980-993. 10.1016/j.cell.2007.09.027.PubMedCentralPubMed

78.

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

79.

Mackay AM, Beck SC, Murphy JM, Barry FP, Chichester CO, Pittenger MF: Chondrogenic differentiation of cultured human mesenchymal stem cells from marrow. Tissue Eng. 1998, 4: 415-428. 10.1089/ten.1998.4.415.PubMed

80.

Hecht J, Seitz V, Urban M, Wagner F, Robinson PN, Stiege A, Dieterich C, Kornak U, Wilkening U, Brieske N, Zwingman C, Kidess A, Stricker S, Mundlos S: Detection of novel skeletogenesis target genes by comprehensive analysis of a Runx2^-/- mouse model. Gene Expr Patterns. 2007, 7: 102-112. 10.1016/j.modgep.2006.05.014.PubMed

81.

Javed A, Bae JS, Afzal F, Gutierrez S, Pratap J, Zaidi SK, Lou Y, van Wijnen AJ, Stein JL, Stein GS, Lian JB: Structural coupling of Smad and Runx2 for execution of the BMP2 osteogenic signal. J Biol Chem. 2008, 283: 8412-8422. 10.1074/jbc.M705578200.PubMedCentralPubMed

82.

Leboy P, Grasso-Knight G, D'Angelo M, Volk SW, Lian JV, Drissi H, Stein GS, Adams SL: Smad-Runx interactions during chondrocyte maturation. J Bone Joint Surg Am. 2001, 83A (Suppl 1): S15-S22.

83.

Hjelmeland AB, Schilling SH, Guo X, Quarles D, Wang XF: Loss of Smad3- mediated negative regulation of Runx2 activity leads to an alteration in cell fate determination. Mol Cell Biol. 2005, 25: 9460-9468. 10.1128/MCB.25.21.9460-9468.2005.PubMedCentralPubMed

84.

Blaney Davidson EN, Vitters EL, Kraan van der PM, Berg van den WB: Expression of transforming growth factor-beta (TGFβ) and the TGFβ signalling molecule SMAD-2P in spontaneous and instability-induced osteoarthritis: role in cartilage degradation, chondrogenesis and osteophyte formation. Ann Rheum Dis. 2006, 65: 1414-1421. 10.1136/ard.2005.045971.PubMed

85.

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

86.

87.

van Beuningen HM, Glansbeek HL, Kraan van der PM, Berg van den WB: Differential effects of local application of BMP-2 or TGF-β1 on both articular cartilage composition and osteophyte formation. Osteoarthritis Cartilage. 1998, 6: 306-317. 10.1053/joca.1998.0129.PubMed

88.

Glansbeek HL, van Beuningen HM, Vitters EL, Kraan van der PM, Berg van den WB: Stimulation of articular cartilage repair in established arthritis by local administration of transforming growth factor-beta into murine knee joints. Lab Invest. 1998, 78: 133-142.PubMed

89.

van Beuningen HM, Kraan van der PM, Arntz OJ, Berg van den WB: In vivo protection against interleukin-1-induced articular cartilage damage by transforming growth factor-beta 1: age-related differences. Ann Rheum Dis. 1994, 53: 593-600. 10.1136/ard.53.9.593.PubMedCentralPubMed

90.

van Beuningen HM, Kraan van der PM, Arntz OJ, Berg van den WB: Protection from interleukin 1 induced destruction of articular cartilage by transforming growth factor beta: studies in anatomically intact cartilage in vitro and in vivo. Ann Rheum Dis. 1993, 52: 185-191. 10.1136/ard.52.3.185.PubMedCentralPubMed

91.

van Beuningen HM, Glansbeek HL, Kraan van der PM, Berg van den WB: Osteoarthritis-like changes in the murine knee joint resulting from intra-articular transforming growth factor-beta injections. Osteoarthritis Cartilage. 2000, 8: 25-33. 10.1053/joca.1999.0267.PubMed

92.

93.

94.

Tesseur I, Zou K, Esposito L, Bard F, Berber E, Can JV, Lin AH, Crews L, Tremblay P, Mathews P, Mucke L, Masliah E, Wyss-Coray T: Deficiency in neuronal TGF-β signaling promotes neurodegeneration and Alzheimer's pathology. J Clin Invest. 2006, 116: 3060-3069. 10.1172/JCI27341.PubMedCentralPubMed

95.

Das P, Golde T: Dysfunction of TGF-β signaling in Alzheimer's disease. J Clin Invest. 2006, 116: 2855-2857. 10.1172/JCI30284.PubMedCentralPubMed

96.

Zhang H, Zou K, Tesseur I, Wyss-Coray T: Small molecule TGF-β mimetics as potential neuroprotective factors. Curr Alzheimer Res. 2005, 2: 183-186. 10.2174/1567205053585756.PubMed

97.

Glaser KB, Li J, Aakre ME, Morgan DW, Sheppard G, Stewart KD, Pollock J, Lee P, O'Connor CZ, Anderson SN, Mussatto DJ, Wegner CW, Moses HL: Transforming growth factor beta mimetics: discovery of 7-[4-(4-cyanophenyl)phenoxy]-heptanohydroxamic acid, a biaryl hydroxamate inhibitor of histone deacetylase. Mol Cancer Ther. 2002, 1: 759-768.PubMed

98.

Bernard DJ, Lee KB, Santos MM: Activin B can signal through both ALK4 and ALK7 in gonadotrope cells. Reprod Biol Endocrinol. 2006, 13: 52-10.1186/1477-7827-4-52.

99.

Fernandez L, Sanz-Rodriguez F, Blanco FJ, Bernabeu C, Botella LM: Hereditary hemorrhagic telangiectasia, a vascular dysplasia affecting the TGF-β signaling pathway. Clin Med Res. 2006, 4: 66-78. 10.3121/cmr.4.1.66.

100.

Li X, Ionescu AM, Schwarz EM, Zhang X, Drissi H, Puzas JE, Rosier RN, Zuscik MJ, O'Keefe RJ: Smad6 is induced by BMP-2 and modulates chondrocyte differentiation. J Orthop Res. 2003, 21: 908-913. 10.1016/S0736-0266(03)00008-1.PubMed

101.

Iwai T, Murai J, Yoshikawa H, Tsumaki N: Smad7 inhibits chondrocyte differentiation at multiple steps during endochondral bone formation and down-regulates p38 MAPK pathways. J Biol Chem. 2008, 283: 27154-27164. 10.1074/jbc.M801175200.PubMed

102.

103.

Inoue Y, Imamura T: Regulation of TGF-β family signaling by E3 ubiquitin ligases. Cancer Sci. 2008, 99: 2107-2112. 10.1111/j.1349-7006.2008.00925.x.PubMed

Title: A role for age-related changes in TGFβ signaling in aberrant chondrocyte differentiation and osteoarthritis
Authors: Peter M van der Kraan
Esmeralda N Blaney Davidson
Wim B van den Berg
Publication date: 01-02-2010
Publisher: BioMed Central
Published in: Arthritis Research & Therapy / Issue 1/2010
Electronic ISSN: 1478-6362
DOI: https://doi.org/10.1186/ar2896

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

Illustration of figure on mountain summit/© Orapun / Stock.adobe.com, STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2010

RNAi-mediated CD40-CD154 interruption promotes tolerance in autoimmune arthritis

Bisphosphonates and risk of atrial fibrillation: a meta-analysis

From the item to the outcome: the promising prospects of PROMIS

c-Fms-mediated differentiation and priming of monocyte lineage cells play a central role in autoimmune arthritis

A Rac1 inhibitory peptide suppresses antibody production and paw swelling in the murine collagen-induced arthritis model of rheumatoid arthritis

High-density lipoproteins downregulate CCL2 production in human fibroblast-like synoviocytes stimulated by urate crystals

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage