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

By Peter M van der Kraan, Esmeralda N Blaney Davidson and Wim B van den Berg


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

Topics: Review
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  1. (2008). A: ALK1 opposes ALK5/ Smad3 signaling and expression of extracellular matrix components in human chondrocytes. J Bone Miner Res
  2. (2000). A: Association of transforming growth factor beta 1 genotype with spinal osteophytosis in Japanese women. Arthritis Rheum
  3. (2006). 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
  4. (2009). Activation of β-catenin signaling in articular chondrocytes leads to osteoarthritis-like phenotype in adult beta-catenin conditional activation mice. J Bone Miner Res
  5. (2001). Anabolic and catabolic gene expression pattern analysis in normal versus osteoarthritic cartilage using complementary DNA-array technology. Arthritis Rheum
  6. (2009). Asahara H: Smad3 activates the Sox9-dependent transcription on chromatin.
  7. (2003). Bhoola KD: Genealogy, expression, and cellular function of transforming growth factor-beta. Pharmacol Ther
  8. (1993). Bogoch E: Osteoarthritis in the human knee: a dynamic process of cartilage matrix degradation, synthesis and reorganization. Agents Actions Suppl
  9. (2008). Boumediene K: Interleukin-1 and transforming growth factor-beta 1 as crucial factors in osteoarthritic cartilage metabolism. Connect Tissue Res
  10. (1992). BW: Diff erential eff ect of transforming growth factor beta on freshly isolated and cultured articular chondrocytes. J
  11. (1981). Catabolin – a cartilage catabolic factor from synovium. Clin Orthop Relat Res
  12. (2000). Chondrocyte diff erentiation in human osteoarthritis: expression of osteocalcin in normal and osteoarthritic cartilage and bone. Calcif Tissue Int
  13. (2004). Cooperation between TGF-β and Wnt pathways during chondrocyte and adipocyte diff erentiation of human marrow stromal cells. J Bone Miner Res
  14. (2002). DB: Bone defects in latent TGF-β binding protein (Ltbp)-3 null mice, a role for Ltbp in TGFβpresentation.
  15. (2007). De Robertis EM: Integrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signal. Cell
  16. (2005). den Berg WB: Reduced transforming growth factor-beta signaling in cartilage of old mice: role in impaired repair capacity. Arthritis Res Ther
  17. (2001). Deng CX: TGF-β/Smad3 signals repress chondrocyte hypertrophic diff erentiation and are required for maintaining articular cartilage.
  18. (2009). der Kraan PM: Increase in ALK1/ALK5 ratio as a cause for elevated MMP-13 expression in osteoarthritis in humans and mice.
  19. (1993). DJ: Evidence for an age-related dysfunction in the antiproliferative response to transforming growth factor-beta in vascular smooth muscle cells. Mol Biol Cell
  20. (2006). 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
  21. (2009). FS: Infl ammation induction of Dickkopf-1 mediates chondrocyte apoptosis in osteoarthritic joint. van der Kraan et al.
  22. (2006). Golde T: Dysfunction of TGF-β signaling in Alzheimer’s disease.
  23. (1997). HL: Expression of a truncated, kinase defective TGF-beta type II receptor in mouse skeletal tissue promotes terminal chondrocyte diff erentiation and osteoarthritis.
  24. (2002). 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
  25. (1997). I: Diff erential response of articular cartilage from young growing and mature old mice to IL-1 and TGF-β. Arch Gerontol Geriatr
  26. (2005). Ikegawa S: An aspartic acid repeat polymorphism in asporin inhibits chondrogenesis and increases susceptibility to osteoarthritis. Nat Genet
  27. (2008). Inhibition of β-catenin signaling in articular chondrocytes results in articular cartilage destruction. Arthritis Rheum
  28. (2007). Integrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signal. Cell
  29. (1994). Interleukin-1 beta-modulated gene expression in immortalized human chondrocytes.
  30. (1986). Interleukin-1 stimulates the secretion of proteoglycan- and collagendegrading proteases by rabbit articular chondrocytes. Clin Immunol Immunopathol
  31. (2003). 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 Chem
  32. (2008). JB: Structural coupling of Smad and Runx2 for execution of the BMP2 osteogenic signal.
  33. (2005). JH: TGFβ1 activates two distinct type I receptors in neurons: implications for neuronal NF-κB signaling.
  34. (1998). JP: Cell-cycle-dependent expression of transforming growth factor beta type I receptor correlates with diff erential proliferative eff ects of TGFβ1 in articular chondrocytes. Exp Cell Res
  35. (1991). JP: Characterization of proteoglycans synthesized by rabbit articular chondrocytes in response to transforming growth factor-beta (TGF-β). Biochim Biophys Acta
  36. (1991). JP: Diff erential response of cultured rabbit articular chondrocytes (RAC) to transforming growth factor beta (TGF-β) – evidence for a role of serum factors.
  37. (1992). JP: Eff ect of transforming growth factor-beta 1 (TGF-β 1) on matrix synthesis by monolayer cultures of rabbit articular chondrocytes during the dediff erentiation process. Exp Cell Res
  38. (1986). JP: Interleukin-1 inhibits the synthesis of collagen by fi broblasts. Biochem Int
  39. (1993). JP: Rabbit articular chondrocytes (RAC) express distinct transforming growth factor-beta receptor phenotypes as a function of cell cycle phases. Exp Cell Res
  40. (1992). 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.
  41. (1988). JP: Transforming growth factor beta stimulates collagen and glycosaminoglycan biosynthesis in cultured rabbit articular chondrocytes. FEBS Lett
  42. (2000). KA: Autocrine regulation of collagenase 3 (matrix metalloproteinase 13) during osteoarthritis. Arthritis Rheum
  43. (2001). Latent-TGF-β: an overview. Mol Cell Biochem
  44. (2006). LM: Hereditary hemorrhagic telangiectasia, a vascular dysplasia aff ecting the TGF-β signaling pathway. Clin Med Res
  45. (1986). Loyau G: Eff ect of a interleukin-1 like factor (mononuclear cell factor) on proteoglycan synthesis in cultured human articular chondrocytes. Biochem Biophys Res Commun
  46. (2000). mediate transforming growth factor-beta1-induced inhibition of chondrocyte maturation. Endocrinology
  47. (1998). MF: Chondrogenic diff erentiation of cultured human mesenchymal stem cells from marrow. Tissue Eng
  48. (1993). MK: Type X collagen expression in osteoarthritic and rheumatoid articular cartilage. Virchows Arch B Cell Pathol Incl Mol Pathol
  49. (2006). MM: Activin B can signal through both ALK4 and ALK7 in gonadotrope cells. Reprod Biol Endocrinol
  50. (2007). Mundlos S: Detection of novel skeletogenesis target genes by comprehensive analysis of a Runx2–/– mouse model. Gene Expr Patterns
  51. (2000). Nah H: Activation of annexin II and V expression, terminal diff erentiation, mineralization and apoptosis in human osteoarthritic cartilage. Osteoarthritis Cartilage
  52. (2009). Non-Smad pathways in TGF-βsignaling. Cell Res
  53. (2004). Nuckolls GH: Regulation of MMP-13 expression by RUNX2 and FGF2 in osteoarthritic cartilage. Osteoarthritis Cartilage
  54. (2003). O’keefe RJ: Retinoic acid stimulates chondrocyte diff erentiation and enhances bone morphogenetic protein eff ects through induction of
  55. (2003). 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.
  56. (2006). O’Keefe RJ: Smad3-defi cient chondrocytes have enhanced BMP signaling and accelerated diff erentiation. J Bone Miner Res
  57. (2003). O’keefe RJ: Smad6 is induced by BMP-2 and modulates chondrocyte diff erentiation.
  58. (2008). Odgren PR: BMP-5 expression increases during chondrocyte diff erentiation in vivo and in vitro and promotes proliferation and cartilage matrix synthesis in primary chondrocyte cultures.
  59. (2009). Over-expression of c-maf by chondrocytes in osteoarthritis.
  60. Pathophysiology of osteoarthritis. Osteoarthritis Cartilage 2004, 12(Suppl A):S31-S33.
  61. (2004). 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.
  62. (2003). Reddi AH: Bone morphogenetic protein signaling in articular chondrocyte diff erentiation. Biochem Biophys Res Commun
  63. (2008). Regulation of TGF-β family signaling by E3 ubiquitin ligases. Cancer Sci
  64. (2006). Replication of the association of the aspartic acid repeat polymorphism in the asporin gene with knee-osteoarthritis susceptibility in Han Chinese. J Genet
  65. (2004). RN: 5-Azacytidine alters TGF-βand BMP signaling and induces maturation in articular chondrocytes.
  66. (2001). SL: Smad–Runx interactions during chondrocyte maturation.
  67. (2004). SM: Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossifi cation.
  68. (2006). SP: Nonoverlapping expression patterns of ALK1 and ALK5 reveal distinct roles of each receptor in vascular development. Lab Invest
  69. (2002). 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.
  70. (2003). ten Dijke P: Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFbeta/ALK5 signaling. Mol Cell
  71. (2002). ten Dijke P: Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors.
  72. (2005). TGFβ inhibits IL-1-induced iNOS expression and NO production in immortalized chondrocytes. Infl amm Res
  73. (1992). The interleukin-1 receptor in normal and osteoarthritic human articular chondrocytes. Identifi cation as the type I receptor and analysis of binding kinetics and biologic function. Arthritis Rheum
  74. (1996). The new collagenase, collagenase-3, is expressed and synthesized by human chondrocytes but not by synoviocytes. A role in osteoarthritis.
  75. (1999). The role of cytokines as infl ammatory mediators in osteoarthritis: lessons from animal models. Connect Tissue Res
  76. (2001). The type I TGF-βreceptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. Nat Cell Biol 2008, 10:1199-1207. van der Kraan et al.
  77. (1988). Transforming growth factor beta regulates the metabolism of proteoglycans in bovine cartilage organ cultures.
  78. (1994). Transforming growth factor-beta (TGF-β) and articular chondrocytes. Ann Endocrinol (Paris)
  79. (1991). Transforming growth factor-beta 1 stimulates synthesis of proteoglycan aggregates in calf articular cartilage organ cultures. Arch Biochem Biophys
  80. (2004). Tsumaki N: Smad6/Smurf1 overexpression in cartilage delays chondrocyte hypertrophy and causes dwarfi sm with osteopenia.
  81. (2008). Tsumaki N: Smad7 inhibits chondrocyte diff erentiation at multiple steps during endochondral bone formation and down-regulates p38 MAPK pathways.
  82. (2005). van den Berg WB: Elucidation of IL-1/TGF-β interactions in mouse chondrocyte cell line by genome-wide gene expression. Osteoarthritis Cartilage
  83. (2003). Veale DJ: Turnover of type II collagen and aggrecan in cartilage matrix at the onset of infl ammatory arthritis in humans: relationship to mediators of systemic and local infl ammation. Arthritis Rheum
  84. (1998). WB: Diff erential eff ects of local application of BMP-2 or TGF-β 1 on both articular cartilage composition and osteophyte formation. Osteoarthritis Cartilage
  85. (1997). WB: Early elevation of transforming growth factor-beta, decorin, and biglycan mRNA levels during cartilage matrix restoration after mild proteoglycan depletion. J
  86. (1994). WB: In vivo protection against interleukin-1-induced articular cartilage damage by transforming growth factor-beta 1: age-related diff erences. Ann Rheum Dis
  87. (2002). WB: Loss of transforming growth factor counteraction on interleukin 1 mediated eff ects in cartilage of old mice. Ann Rheum Dis
  88. (2000). WB: Osteoarthritis-like changes in the murine knee joint resulting from intraarticular transforming growth factor-beta injections. Osteoarthritis Cartilage
  89. (1993). 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
  90. (1998). WB: Stimulation of articular cartilage repair in established arthritis by local administration of transforming growth factor-beta into murine knee joints. Lab Invest
  91. (1994). WB: Transforming growth factor-beta 1 stimulates articular chondrocyte proteoglycan synthesis and induces osteophyte formation in the murine knee joint. Lab Invest
  92. (2004). Werb Z: Altered endochondral bone development in matrix metalloproteinase 13-defi cient mice. Development
  93. (2006). Wyss-Coray T: Defi ciency in neuronal TGF-β signaling promotes neurodegeneration and Alzheimer’s pathology. J Invest
  94. (2005). Wyss-Coray T: Small molecule TGF-β mimetics as potential neuroprotective factors. Curr Alzheimer Res
  95. (2005). XF: Loss of Smad3-mediated negative regulation of Runx2 activity leads to an alteration in cell fate determination. Mol Cell Biol
  96. (2006). YG: Distinct regulation of gene expression in human endothelial cells by TGF-β and its receptors. Microvasc Res
  97. (2003). Zuscik MJ, O’Keefe RJ: Smad6 is induced by BMP-2 and modulates chondrocyte diff erentiation.