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Transforming Growth Factor-Beta Induced Chrondrogenic Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells: Role of Smad Signaling Pathways

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Stem Cells and Cancer Stem Cells, Volume 10

Part of the book series: Stem Cells and Cancer Stem Cells ((STEM,volume 10))

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Abstract

Mesenchymal stem cells can be differentiated to a number of lineages, adipocytes, osteoblasts and also chondrocytes. In the differentiation process of chondrocytes, members of the TGF-β superfamily play a decisive role. These factors control not only lineage determination but also the subsequent steps of chondrocyte differentiation. The intracellular signaling molecules of this family, the Smads, are indispensable to regulate, in concerted action with Runx2, this process. Specific Smad subtypes play differing roles in the various stages of chondrocyte differentiation. This feature of the Smads can be used to control chondrocyte differentiation and to generate stable cartilage that can be used for repair purposes.

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References

  • Ballock RT, Heydemann A, Wakefield LM, Flanders KC, Roberts AB, Sporn MB (1993) TGF-beta 1 prevents hypertrophy of epiphyseal chondrocytes: regulation of gene expression for cartilage matrix proteins and metalloproteases. Dev Biol 158:414–429

    Article  PubMed  CAS  Google Scholar 

  • 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 182:7937–7945

    Article  PubMed  CAS  Google Scholar 

  • Bohme K, Winterhalter KH, Bruckner P (1995) Terminal differentiation of chondrocytes in culture is a spontaneous process and is arrested by transforming growth factor-beta 2 and basic fibroblast growth factor in synergy. Exp Cell Res 216:191–198

    Article  PubMed  CAS  Google Scholar 

  • Chimal-Monroy J, Diaz de Leon L (1997) Differential effects of transforming growth factors beta 1, beta 2, beta 3 and beta 5 on chondrogenesis in mouse limb bud mesenchymal cells. Int J Dev Biol 41:91–102

    PubMed  CAS  Google Scholar 

  • Finnson KW, Parker WL, ten Dijke P, Thorikay M, Philip A (2008) ALK1 opposes ALK5/Smad3 signaling and expression of extracellular matrix components in human chondrocytes. J Bone Miner Res 23:896–906

    Article  PubMed  CAS  Google Scholar 

  • Goumans MJ, Lebrin F, Valdimarsdottir G (2003) Controlling the angiogenic switch: a balance between two distinct TGF-b receptor signaling pathways. Trends Cardiovasc Med 13:301–307

    Article  PubMed  CAS  Google Scholar 

  • Haas AR, Tuan RS (1999) Chondrogenic differentiation of murine C3H10T1/2 multipotential mesenchymal cells: II. Stimulation by bone morphogenetic protein-2 requires modulation of N-cadherin expression and function. Differentiation 64:77–89

    Article  PubMed  CAS  Google Scholar 

  • Hatakeyama Y, Nguyen J, Wang X, Nuckolls GH, Shum L (2003) Smad signaling in mesenchymal and chondroprogenitor cells. J Bone Joint Surg Am 85-A(Suppl 3):13–18

    PubMed  Google Scholar 

  • 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 (2007) Detection of novel skeletogenesis target genes by comprehensive analysis of a Runx2(-/-) mouse model. Gene Expr Patterns 7:102–112

    Article  PubMed  CAS  Google Scholar 

  • Heldens GT, Blaney Davidson EN, Vitters EL, Schreurs BW, Piek E, van den Berg WB, van der Kraan PM (2012) Catabolic factors and osteoarthritis-conditioned medium inhibit chondrogenesis of human mesenchymal stem cells. Tissue Eng Part A 18(1–2):45–54

    Article  PubMed  CAS  Google Scholar 

  • Hellingman CA, Davidson EN, Koevoet W, Vitters EL, van den Berg WB, van Osch GJ, van der Kraan PM (2011) Smad signaling determines chondrogenic differentiation of bone-marrow-derived mesenchymal stem cells: inhibition of Smad1/5/8P prevents terminal differentiation and calcification. Tissue Eng Part A 17(7–8):1157–1167

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Javed A, Afzal F, Bae JS, Gutierrez S, Zaidi K, Pratap J, van Wijnen AJ, Stein JL, Stein GS, Lian JB (2009) Specific residues of RUNX2 are obligatory for formation of BMP2-induced RUNX2-SMAD complex to promote osteoblast differentiation. Cells Tissues Organs 189:133–137

    Article  PubMed  CAS  Google Scholar 

  • Jin EJ, Park KS, Kim D, Lee YS, Sonn JK, Jung JC, Bang OS, Kang SS (2010) TGF-beta3 inhibits chondrogenesis by suppressing precartilage condensation through stimulation of N-cadherin shedding and reduction of cRREB-1 expression. Mol Cells 29:425–432

    Article  PubMed  CAS  Google Scholar 

  • Joyce ME, Roberts AB, Sporn MB, Bolander ME (1990) Transforming growth factor-beta and the initiation of chondrogenesis and osteogenesis in the rat femur. J Cell Biol 110:2195–2207

    Article  PubMed  CAS  Google Scholar 

  • Ju W, Hoffmann A, Verschueren K, Tylzanowski P, Kaps C, Gross G, Huylebroeck D (2000) The bone morphogenetic protein 2 signaling mediator Smad1 participates predominantly in osteogenic and not in chondrogenic differentiation in mesenchymal progenitors C3H10T1/2. J Bone Miner Res 15:1889–1899

    Article  PubMed  CAS  Google Scholar 

  • Kawai J, Akiyama H, Shigeno C, Ito H, Konishi J, Nakamura T (1999) Effects of transforming growth factor-beta signaling on chondrogenesis in mouse chondrogenic EC cells, ATDC5. Eur J Cell Biol 78:707–714

    Article  PubMed  CAS  Google Scholar 

  • Kim HJ, Im GI (2009) Combination of transforming growth factor-beta2 and bone morphogenetic protein 7 enhances chondrogenesis from adipose tissue-derived mesenchymal stem cells. Tissue Eng Part A 15:1543–1551

    Article  PubMed  CAS  Google Scholar 

  • Leboy PS (2006) Regulating bone growth and development with bone morphogenetic proteins. Ann N Y Acad Sci 1068:14–18

    Article  PubMed  CAS  Google Scholar 

  • Leonard CM, Fuld HM, Frenz DA, Downie SA, Massague J, Newman SA (1991) Role of transforming growth factor-beta in chondrogenic pattern formation in the embryonic limb: stimulation of mesenchymal condensation and fibronectin gene expression by exogenenous TGF-beta and evidence for endogenous TGF-beta-like activity. Dev Biol 145:99–109

    Article  PubMed  CAS  Google Scholar 

  • Miyazono K, Maeda S, Imamura T (2004) Coordinate regulation of cell growth and differentiation by TGF-beta superfamily and Runx proteins. Oncogene 23:4232–4237

    Article  PubMed  CAS  Google Scholar 

  • Nakamura K, Shirai T, Morishita S, Uchida S, Saeki-Miura K, Makishima F (1999) p38 mitogen-activated protein kinase functionally contributes to chondrogenesis induced by growth/differentiation factor-5 in ATDC5 cells. Exp Cell Res 250:351–363

    Article  PubMed  CAS  Google Scholar 

  • Nonaka K, Shum L, Takahashi I, Takahashi K, Ikura T, Dashner R, Nuckolls GH, Slavkin HC (1999) Convergence of the BMP and EGF signaling pathways on Smad1 in the regulation of chondrogenesis. Int J Dev Biol 43:795–807

    PubMed  CAS  Google Scholar 

  • Pizette S, Niswander L (2000) BMPs are required at two steps of limb chondrogenesis: formation of prechondrogenic condensations and their differentiation into chondrocytes. Dev Biol 219:237–249

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Roark EF, Greer K (1994) Transforming growth factor-beta and bone morphogenetic protein-2 act by distinct mechanisms to promote chick limb cartilage differentiation in vitro. Dev Dyn 200:103–116

    Article  PubMed  CAS  Google Scholar 

  • Rui YF, DU L, Wang Y, Wang Y, Lui PP, Tang TT, Chan KM, Dai KR (2010) Bone morphogenetic protein 2 promotes transforming growth factor beta3-induced chondrogenesis of human osteoarthritic synovium-derived stem cells. Chin Med J (Engl) 123:3040–3048

    CAS  Google Scholar 

  • Sato S, Kimura A, Ozdemir J, Asou Y, Miyazaki M, Jinno T, Ae K, Liu X, Osaki M, Takeuchi Y, Fukumoto S, Kawaguchi H, Haro H, Shinomiya K, Karsenty G, Takeda S (2008) The distinct role of the Runx proteins in chondrocyte differentiation and intervertebral disc degeneration: findings in murine models and in human disease. Arthritis Rheum 58:2764–2775

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Seyedin SM, Thomas TC, Thompson AY, Rosen DM, Piez KA (1985) Purification and characterization of two cartilage-inducing factors from bovine demineralized bone. Proc Natl Acad Sci U S A 82:2267–2271

    Article  PubMed  CAS  Google Scholar 

  • Seyedin SM, Thompson AY, Bentz H, Rosen DM, McPherson JM, Conti A, Siegel NR, Galluppi GR, Piez KA (1986) Cartilage-inducing factor-A. Apparent identity to transforming growth factor-beta. J Biol Chem 261:5693–5695

    PubMed  CAS  Google Scholar 

  • Song JJ, Aswad R, Kanaan RA, Rico MC, Owen TA, Barbe MF, Safadi FF, Popoff SN (2007) Connective tissue growth factor (CTGF) acts as a downstream mediator of TGF-beta1 to induce mesenchymal cell condensation. J Cell Physiol 210:398–410

    Article  PubMed  CAS  Google Scholar 

  • Watanabe H, de Caestecker MP, Yamada Y (2001) Transcriptional cross-talk between Smad, ERK1/2, and p38 mitogen-activated protein kinase pathways regulates transforming growth factor-beta-induced aggrecan gene expression in chondrogenic ATDC5 cells. J Biol Chem 276:14466–14473

    PubMed  CAS  Google Scholar 

  • 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 153:35–46

    Article  PubMed  CAS  Google Scholar 

  • Zhang X, Ziran N, Goater JJ, Schwarz EM, Puzas JE, Rosier RN, Zuscik M, Drissi H, O’Keefe RJ (2004) Primary murine limb bud mesenchymal cells in long-term culture complete chondrocyte differentiation: TGF-beta delays hypertrophy and PGE2 inhibits terminal differentiation. Bone 34:809–817

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Rheumatology, Radboud University Nijmegen Medical Centre, 910, Nijmegen, 9500HB, The Netherlands

    Peter M. van der Kraan

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  1. Peter M. van der Kraan
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Correspondence to Peter M. van der Kraan .

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  1. , Kean University, Room 213, Library building, Morris Avenue 1000, Union, 07083, New Jersey, USA

    M.A. Hayat

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van der Kraan, P.M. (2013). Transforming Growth Factor-Beta Induced Chrondrogenic Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells: Role of Smad Signaling Pathways. In: Hayat, M. (eds) Stem Cells and Cancer Stem Cells, Volume 10. Stem Cells and Cancer Stem Cells, vol 10. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6262-6_8

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