Cellular and Molecular Life Sciences

, Volume 73, Issue 7, pp 1489–1501 | Cite as

RECK (reversion-inducing cysteine-rich protein with Kazal motifs) regulates migration, differentiation and Wnt/β-catenin signaling in human mesenchymal stem cells

  • Christian Mahl
  • Virginia Egea
  • Remco T. A. Megens
  • Thomas Pitsch
  • Donato Santovito
  • Christian Weber
  • Christian RiesEmail author
Original Article


The membrane-anchored glycoprotein RECK (reversion-inducing cysteine-rich protein with Kazal motifs) inhibits expression and activity of certain matrix metalloproteinases (MMPs), thereby suppressing tumor cell metastasis. However, RECK’s role in physiological cell function is largely unknown. Human mesenchymal stem cells (hMSCs) are able to differentiate into various cell types and represent promising tools in multiple clinical applications including the regeneration of injured tissues by endogenous or transplanted hMSCs. RNA interference of RECK in hMSCs revealed that endogenous RECK suppresses the transcription and biosynthesis of tissue inhibitor of metalloproteinases (TIMP)-2 but does not influence the expression of MMP-2, MMP-9, membrane type (MT)1-MMP and TIMP-1 in these cells. Knockdown of RECK in hMSCs promoted monolayer regeneration and chemotactic migration of hMSCs, as demonstrated by scratch wound and chemotaxis assay analyses. Moreover, expression of endogenous RECK was upregulated upon osteogenic differentiation and diminished after adipogenic differentiation of hMSCs. RECK depletion in hMSCs reduced their capacity to differentiate into the osteogenic lineage whereas adipogenesis was increased, demonstrating that RECK functions as a master switch between both pathways. Furthermore, knockdown of RECK in hMSCs attenuated the Wnt/β-catenin signaling pathway as indicated by reduced stability and impaired transcriptional activity of β-catenin. The latter was determined by analysis of the β-catenin target genes Dickkopf1 (DKK1), axis inhibition protein 2 (AXIN2), runt-related transcription factor 2 (RUNX2) and a luciferase-based β-catenin-activated reporter (BAR) assay. Our findings demonstrate that RECK is a regulator of hMSC functions suggesting that modulation of RECK may improve the development of hMSC-based therapeutical approaches in regenerative medicine.


RECK hMSC Chemotactic migration Osteogenic differentiation Canonical Wnt/β-catenin signaling 



Alkaline phosphatase


Axis inhibition protein 2


β-Catenin-activated reporter


Displacement of the center of mass




Extracellular matrix


Forward migration index


Glyceraldehyde-3-phosphate dehydrogenase


Human mesenchymal stem cell


Lymphoid enhancer factor


Matrix metalloproteinase


Mesenchymal stem cell growth medium


Membrane-type 1 matrix metalloproteinase


Peroxisome proliferator-activated receptor γ


Quantitative real-time polymerase chain reaction


Reversion-inducing cysteine-rich protein with Kazal motifs


Runt-related transcription factor 2


Small interfering RNA


T cell factor


Tissue inhibitor of metalloproteinase


Wingless-type mouse mammary tumor virus integration site



Microscopic analysis and data evaluation of the scratch assay were performed with kind help from Maximilian Saller. The BAR was established and kindly provided by Randall T. Moon (University of Washington, USA). This work was funded by grants from the Institute of Cardiovascular Prevention, Ludwig-Maximilians-University of Munich and was supported by Deutsche Forschungsgemeinschaft (SFB 1123-A1 and Z1).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Horwitz EM, Le BK, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC, Deans RJ, Krause DS, Keating A (2005) Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy. 7(5):393–395CrossRefPubMedGoogle Scholar
  2. 2.
    Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284(5411):143–147CrossRefPubMedGoogle Scholar
  3. 3.
    Egea V, von Baumgarten L, Schichor C, Berninger B, Popp T, Neth P, Goldbrunner R, Kienast Y, Winkler F, Jochum M, Ries C (2011) TNF-alpha respecifies human mesenchymal stem cells to a neural fate and promotes migration toward experimental glioma. Cell Death Differ 18(5):853–863CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM (2002) Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418(6893):41–49CrossRefPubMedGoogle Scholar
  5. 5.
    Mackenzie TC, Flake AW (2001) Human mesenchymal stem cells persist, demonstrate site-specific multipotential differentiation, and are present in sites of wound healing and tissue regeneration after transplantation into fetal sheep. Blood Cells Mol Dis 27(3):601–604CrossRefPubMedGoogle Scholar
  6. 6.
    Wu GD, Nolta JA, Jin YS, Barr ML, Yu H, Starnes VA, Cramer DV (2003) Migration of mesenchymal stem cells to heart allografts during chronic rejection. Transplantation 75(5):679–685CrossRefPubMedGoogle Scholar
  7. 7.
    Ryan JM, Barry F, Murphy JM, Mahon BP (2007) Interferon-gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin Exp Immunol 149(2):353–363CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Mankani MH, Kuznetsov SA, Wolfe RM, Marshall GW, Robey PG (2006) In vivo bone formation by human bone marrow stromal cells: reconstruction of the mouse calvarium and mandible. Stem Cells 24(9):2140–2149CrossRefPubMedGoogle Scholar
  9. 9.
    Martens TP, Godier AF, Parks JJ, Wan LQ, Koeckert MS, Eng GM, Hudson BI, Sherman W, Vunjak-Novakovic G (2009) Percutaneous cell delivery into the heart using hydrogels polymerizing in situ. Cell Transplant 18(3):297–304CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Zhao CP, Zhang C, Zhou SN, Xie YM, Wang YH, Huang H, Shang YC, Li WY, Zhou C, Yu MJ, Feng SW (2007) Human mesenchymal stromal cells ameliorate the phenotype of SOD1-G93A ALS mice. Cytotherapy 9(5):414–426CrossRefPubMedGoogle Scholar
  11. 11.
    Fiorina P, Jurewicz M, Augello A, Vergani A, Dada S, La Rosa S, Selig M, Godwin J, Law K, Placidi C, Smith RN, Capella C, Rodig S, Adra CN, Atkinson M, Sayegh MH, Abdi R (2009) Immunomodulatory function of bone marrow-derived mesenchymal stem cells in experimental autoimmune type 1 diabetes. J Immunol 183(2):993–1004CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Ringden O, Uzunel M, Rasmusson I, Remberger M, Sundberg B, Lonnies H, Marschall HU, Dlugosz A, Szakos A, Hassan Z, Omazic B, Aschan J, Barkholt L, Le Blanc K (2006) Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation 81(10):1390–1397CrossRefPubMedGoogle Scholar
  13. 13.
    Tanaka F, Tominaga K, Ochi M, Tanigawa T, Watanabe T, Fujiwara Y, Ohta K, Oshitani N, Higuchi K, Arakawa T (2008) Exogenous administration of mesenchymal stem cells ameliorates dextran sulfate sodium-induced colitis via anti-inflammatory action in damaged tissue in rats. Life Sci 83(23–24):771–779CrossRefPubMedGoogle Scholar
  14. 14.
    Ries C, Egea V, Karow M, Kolb H, Jochum M, Neth P (2007) MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells: differential regulation by inflammatory cytokines. Blood 109(9):4055–4063CrossRefPubMedGoogle Scholar
  15. 15.
    Malinowski M, Pietraszek K, Perreau C, Boguslawski M, Decot V, Stoltz JF, Vallar L, Niewiarowska J, Cierniewski C, Maquart FX, Wegrowski Y, Brezillon S (2012) Effect of lumican on the migration of human mesenchymal stem cells and endothelial progenitor cells: involvement of matrix metalloproteinase-14. PLoS ONE 7(12):e50709CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Ponte AL, Ribeiro-Fleury T, Chabot V, Gouilleux F, Langonne A, Herault O, Charbord P, Domenech J (2012) Granulocyte-colony-stimulating factor stimulation of bone marrow mesenchymal stromal cells promotes CD34+ cell migration via a matrix metalloproteinase-2-dependent mechanism. Stem Cells Dev 21(17):3162–3172CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Ho IA, Yulyana Y, Sia KC, Newman JP, Guo CM, Hui KM, Lam PY (2014) Matrix metalloproteinase-1-mediated mesenchymal stem cell tumor tropism is dependent on crosstalk with stromal derived growth factor 1/C-X-C chemokine receptor 4 axis. Faseb j 28(10):4359–4368CrossRefPubMedGoogle Scholar
  18. 18.
    Olson MW, Gervasi DC, Mobashery S, Fridman R (1997) Kinetic analysis of the binding of human matrix metalloproteinase-2 and -9 to tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. J Biol Chem 272(47):29975–29983CrossRefPubMedGoogle Scholar
  19. 19.
    Butler GS, Butler MJ, Atkinson SJ, Will H, Tamura T, Schade van Westrum S, Crabbe T, Clements J, d’Ortho MP, Murphy G (1998) The TIMP2 membrane type 1 metalloproteinase “receptor” regulates the concentration and efficient activation of progelatinase A. A kinetic study. J Biol Chem 273(2):871–880PubMedGoogle Scholar
  20. 20.
    Salazar KD, Lankford SM, Brody AR (2009) Mesenchymal stem cells produce Wnt isoforms and TGF-beta1 that mediate proliferation and procollagen expression by lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 297(5):L1002–L1011CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Qiu W, Andersen TE, Bollerslev J, Mandrup S, Abdallah BM, Kassem M (2007) Patients with high bone mass phenotype exhibit enhanced osteoblast differentiation and inhibition of adipogenesis of human mesenchymal stem cells. J Bone Miner Res 22(11):1720–1731CrossRefPubMedGoogle Scholar
  22. 22.
    Neth P, Ciccarella M, Egea V, Hoelters J, Jochum M, Ries C (2006) Wnt signaling regulates the invasion capacity of human mesenchymal stem cells. Stem Cells 24(8):1892–1903CrossRefPubMedGoogle Scholar
  23. 23.
    Mao J, Wang J, Liu B, Pan W, Farr GH 3rd, Flynn C, Yuan H, Takada S, Kimelman D, Li L, Wu D (2001) Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol Cell 7(4):801–809CrossRefPubMedGoogle Scholar
  24. 24.
    Molenaar M, van de Wetering M, Oosterwegel M, Peterson-Maduro J, Godsave S, Korinek V, Roose J, Destree O, Clevers H (1996) XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos. Cell 86(3):391–399CrossRefPubMedGoogle Scholar
  25. 25.
    Behrens J, von Kries JP, Kuhl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W (1996) Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 382(6592):638–642CrossRefPubMedGoogle Scholar
  26. 26.
    Niida A, Hiroko T, Kasai M, Furukawa Y, Nakamura Y, Suzuki Y, Sugano S, Akiyama T (2004) DKK1, a negative regulator of Wnt signaling, is a target of the beta-catenin/TCF pathway. Oncogene 23(52):8520–8526CrossRefPubMedGoogle Scholar
  27. 27.
    Jho EH, Zhang T, Domon C, Joo CK, Freund JN, Costantini F (2002) Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol Cell Biol 22(4):1172–1183CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Gaur T, Lengner CJ, Hovhannisyan H, Bhat RA, Bodine PV, Komm BS, Javed A, van Wijnen AJ, Stein JL, Stein GS, Lian JB (2005) Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. J Biol Chem 280(39):33132–33140CrossRefPubMedGoogle Scholar
  29. 29.
    Takahashi C, Sheng Z, Horan TP, Kitayama H, Maki M, Hitomi K, Kitaura Y, Takai S, Sasahara RM, Horimoto A, Ikawa Y, Ratzkin BJ, Arakawa T, Noda M (1998) Regulation of matrix metalloproteinase-9 and inhibition of tumor invasion by the membrane-anchored glycoprotein RECK. Proc Natl Acad Sci U S A 95(22):13221–13226CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Takagi S, Simizu S, Osada H (2009) RECK negatively regulates matrix metalloproteinase-9 transcription. Cancer Res 69(4):1502–1508CrossRefPubMedGoogle Scholar
  31. 31.
    Oh J, Takahashi R, Kondo S, Mizoguchi A, Adachi E, Sasahara RM, Nishimura S, Imamura Y, Kitayama H, Alexander DB, Ide C, Horan TP, Arakawa T, Yoshida H, Nishikawa S, Itoh Y, Seiki M, Itohara S, Takahashi C, Noda M (2001) The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis. Cell 107(6):789–800CrossRefPubMedGoogle Scholar
  32. 32.
    Miki T, Takegami Y, Okawa K, Muraguchi T, Noda M, Takahashi C (2007) The reversion-inducing cysteine-rich protein with Kazal motifs (RECK) interacts with membrane type 1 matrix metalloproteinase and CD13/aminopeptidase N and modulates their endocytic pathways. J Biol Chem 282(16):12341–12352CrossRefPubMedGoogle Scholar
  33. 33.
    Namwat N, Puetkasichonpasutha J, Loilome W, Yongvanit P, Techasen A, Puapairoj A, Sripa B, Tassaneeyakul W, Khuntikeo N, Wongkham S (2011) Downregulation of reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) is associated with enhanced expression of matrix metalloproteinases and cholangiocarcinoma metastases. J Gastroenterol 46(5):664–675CrossRefPubMedGoogle Scholar
  34. 34.
    Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, Hanahan D (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2(10):737–744CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Guo H, Li Q, Li W, Zheng T, Zhao S, Liu Z (2014) MiR-96 downregulates RECK to promote growth and motility of non-small cell lung cancer cells. Mol Cell Biochem 390(1–2):155–160CrossRefPubMedGoogle Scholar
  36. 36.
    Walsh LA, Roy DM, Reyngold M, Giri D, Snyder A, Turcan S, Badwe CR, Lyman J, Bromberg J, King TA, Chan TA (2014) RECK controls breast cancer metastasis by modulating a convergent, STAT3-dependent neoangiogenic switch. Oncogene 34(17):2189–2203Google Scholar
  37. 37.
    Jacomasso T, Trombetta-Lima M, Sogayar MC, Winnischofer SM (2014) Downregulation of reversion-inducing cysteine-rich protein with Kazal motifs in malignant melanoma: inverse correlation with membrane-type 1-matrix metalloproteinase and tissue inhibitor of metalloproteinase 2. Melanoma Res 24(1):32–39CrossRefPubMedGoogle Scholar
  38. 38.
    Hoelters J, Ciccarella M, Drechsel M, Geissler C, Gulkan H, Bocker W, Schieker M, Jochum M, Neth P (2005) Nonviral genetic modification mediates effective transgene expression and functional RNA interference in human mesenchymal stem cells. J Gene Med 7(6):718–728CrossRefPubMedGoogle Scholar
  39. 39.
    Reynolds A, Leake D, Boese Q, Scaringe S, Marshall WS, Khvorova A (2004) Rational siRNA design for RNA interference. Nat Biotechnol 22(3):326–330CrossRefPubMedGoogle Scholar
  40. 40.
    Naumann K, Wehner R, Schwarze A, Petzold C, Schmitz M, Rohayem J (2013) Activation of dendritic cells by the novel Toll-like receptor 3 agonist RGC100. Clin Dev Immunol 2013:283649CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Nolte A, Ott K, Rohayem J, Walker T, Schlensak C, Wendel HP (2013) Modification of small interfering RNAs to prevent off-target effects by the sense strand. N Biotechnol 30(2):159–165CrossRefPubMedGoogle Scholar
  42. 42.
    Egea V, Zahler S, Rieth N, Neth P, Popp T, Kehe K, Jochum M, Ries C (2012) Tissue inhibitor of metalloproteinase-1 (TIMP-1) regulates mesenchymal stem cells through let-7f microRNA and Wnt/beta-catenin signaling. Proc Natl Acad Sci USA 109(6):E309–E316CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Biechele TL, Adams AM, Moon RT (2009) Transcription-based reporters of Wnt/beta-catenin signaling. Cold Spring Harb Protoc 2009(6):pdb prot5223Google Scholar
  44. 44.
    Ries C, Pitsch T, Mentele R, Zahler S, Egea V, Nagase H, Jochum M (2007) Identification of a novel 82 kDa proMMP-9 species associated with the surface of leukaemic cells: (auto-)catalytic activation and resistance to inhibition by TIMP-1. Biochem J 405(3):547–558CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Lipton A, Klinger I, Paul D, Holley RW (1971) Migration of mouse 3T3 fibroblasts in response to a serum factor. Proc Natl Acad Sci USA 68(11):2799–2801CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Heggebo J, Haasters F, Polzer H, Schwarz C, Saller MM, Mutschler W, Schieker M, Prall WC (2014) Aged human mesenchymal stem cells: the duration of bone morphogenetic protein-2 stimulation determines induction or inhibition of osteogenic differentiation. Orthop Rev (Pavia) 6(2):5242CrossRefGoogle Scholar
  47. 47.
    Rayleigh L (1919) XXXI. On the problem of random vibrations, and of random flights in one, two, or three dimensions. Philosophical Magazine Series 6 37(220):321–347Google Scholar
  48. 48.
    Yoshida D, Nomura R, Teramoto A (2008) Regulation of cell invasion and signalling pathways in the pituitary adenoma cell line, HP-75, by reversion-inducing cysteine-rich protein with kazal motifs (RECK). J Neurooncol 89(2):141–150CrossRefPubMedGoogle Scholar
  49. 49.
    Oh J, Seo DW, Diaz T, Wei B, Ward Y, Ray JM, Morioka Y, Shi S, Kitayama H, Takahashi C, Noda M, Stetler-Stevenson WG (2004) Tissue inhibitors of metalloproteinase 2 inhibits endothelial cell migration through increased expression of RECK. Cancer Res 64(24):9062–9069CrossRefPubMedGoogle Scholar
  50. 50.
    Oh J, Diaz T, Wei B, Chang H, Noda M, Stetler-Stevenson WG (2006) TIMP-2 upregulates RECK expression via dephosphorylation of paxillin tyrosine residues 31 and 118. Oncogene 25(30):4230–4234CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Silveira Correa TC, Massaro RR, Brohem CA, Taboga SR, Lamers ML, Santos MF, Maria-Engler SS (2010) RECK-mediated inhibition of glioma migration and invasion. J Cell Biochem 110(1):52–61PubMedGoogle Scholar
  52. 52.
    Miki T, Shamma A, Kitajima S, Takegami Y, Noda M, Nakashima Y, Watanabe K, Takahashi C (2010) The ss1-integrin-dependent function of RECK in physiologic and tumor angiogenesis. Mol Cancer Res 8(5):665–676CrossRefPubMedGoogle Scholar
  53. 53.
    Kimura T, Okada A, Yatabe T, Okubo M, Toyama Y, Noda M, Okada Y (2010) RECK is up-regulated and involved in chondrocyte cloning in human osteoarthritic cartilage. Am J Pathol 176(6):2858–2867CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Lee YM, Lee SH, Lee KB, Nguyen MP, Lee MY, Park GH, Kwon MJ (2013) Silencing of reversion-inducing cysteine-rich protein with Kazal motifs stimulates hyperplastic phenotypes through activation of epidermal growth factor receptor and hypoxia-inducible factor-2alpha. PLoS ONE 8(12):e84520CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Clark JC, Akiyama T, Thomas DM, Labrinidis A, Evdokiou A, Galloway SJ, Kim HS, Dass CR, Choong PF (2011) RECK in osteosarcoma: a novel role in tumour vasculature and inhibition of tumorigenesis in an orthotopic model. Cancer 117(15):3517–3528CrossRefPubMedGoogle Scholar
  56. 56.
    Yoshida Y, Ninomiya K, Hamada H, Noda M (2012) Involvement of the SKP2-p27(KIP1) pathway in suppression of cancer cell proliferation by RECK. Oncogene 31(37):4128–4138CrossRefPubMedGoogle Scholar
  57. 57.
    Accorsi-Mendonca T, Paiva KB, Zambuzzi WF, Cestari TM, Lara VS, Sogayar MC, Taga R, Granjeiro JM (2008) Expression of matrix metalloproteinases-2 and -9 and RECK during alveolar bone regeneration in rat. J Mol Histol 39(2):201–208CrossRefPubMedGoogle Scholar
  58. 58.
    Zambuzzi WF, Yano CL, Cavagis AD, Peppelenbosch MP, Granjeiro JM, Ferreira CV (2009) Ascorbate-induced osteoblast differentiation recruits distinct MMP-inhibitors: RECK and TIMP-2. Mol Cell Biochem 322(1–2):143–150CrossRefPubMedGoogle Scholar
  59. 59.
    Visigalli D, Strangio A, Palmieri D, Manduca P (2010) Hind limb unloading of mice modulates gene expression at the protein and mRNA level in mesenchymal bone cells. BMC Musculoskelet Disord 11:147CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Alexander D, Ardjomandi N, Munz A, Friedrich B, Reinert S (2011) ECM remodelling components regulated during jaw periosteal cell osteogenesis. Cell Biol Int 35(10):973–980CrossRefPubMedGoogle Scholar
  61. 61.
    Chen YH, Yeh FL, Yeh SP, Ma HT, Hung SC, Hung MC, Li LY (2011) Myocyte enhancer factor-2 interacting transcriptional repressor (MITR) is a switch that promotes osteogenesis and inhibits adipogenesis of mesenchymal stem cells by inactivating peroxisome proliferator-activated receptor gamma-2. J Biol Chem 286(12):10671–10680CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    D’Alimonte I, Lannutti A, Pipino C, Di Tomo P, Pierdomenico L, Cianci E, Antonucci I, Marchisio M, Romano M, Stuppia L, Caciagli F, Pandolfi A, Ciccarelli R (2013) Wnt signaling behaves as a “master regulator” in the osteogenic and adipogenic commitment of human amniotic fluid mesenchymal stem cells. Stem Cell Rev 9(5):642–654CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Gattu AK, Swenson ES, Iwakiri Y, Samuel VT, Troiano N, Berry R, Church CD, Rodeheffer MS, Carpenter TO, Chung C (2013) Determination of mesenchymal stem cell fate by pigment epithelium-derived factor (PEDF) results in increased adiposity and reduced bone mineral content. FASEB J 27(11):4384–4394CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G (1997) Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89(5):747–754CrossRefPubMedGoogle Scholar
  65. 65.
    Fedi P, Bafico A, Nieto Soria A, Burgess WH, Miki T, Bottaro DP, Kraus MH, Aaronson SA (1999) Isolation and biochemical characterization of the human Dkk-1 homologue, a novel inhibitor of mammalian Wnt signaling. J Biol Chem 274(27):19465–19472CrossRefPubMedGoogle Scholar
  66. 66.
    Behrens J, Jerchow BA, Wurtele M, Grimm J, Asbrand C, Wirtz R, Kuhl M, Wedlich D, Birchmeier W (1998) Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta. Science 280(5363):596–599CrossRefPubMedGoogle Scholar

Copyright information

© Springer Basel 2015

Authors and Affiliations

  • Christian Mahl
    • 1
  • Virginia Egea
    • 1
  • Remco T. A. Megens
    • 1
    • 2
  • Thomas Pitsch
    • 1
  • Donato Santovito
    • 1
  • Christian Weber
    • 1
    • 2
    • 3
  • Christian Ries
    • 1
    Email author
  1. 1.Institute for Cardiovascular PreventionLudwig-Maximilians-University of MunichMunichGermany
  2. 2.Cardiovascular Research Institute MaastrichtMaastricht UniversityMaastrichtThe Netherlands
  3. 3.German Centre for Cardiovascular ResearchPartner Site Munich Heart AllianceMunichGermany

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