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High glucose microenvironments inhibit the proliferation and migration of bone mesenchymal stem cells by activating GSK3β

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Abstract

Diabetes mellitus involves metabolic changes that can impair bone repair. Bone mesenchymal stem cells (BMSCs) play an important role in bone regeneration. However, the bone regeneration ability of BMSCs is inhibited in high glucose microenvironments. It can be speculated that this effect is due to changes in BMSCs' proliferation and migration ability, because the recruitment of factors with an adequate number of MSCs and the microenvironment around the site of bone injury are required for effective bone repair. Recent genetic evidence has shown that the Cyclin D1 and the CXC receptor 4 (CXCR-4) play important roles in the proliferation and migration of BMSCs. In this study we determined the specific role of glycogen synthase kinase-3β (GSK3β) in the proliferation and migration of BMSCs in high glucose microenvironments. The proliferation and migration ability of BMSCs were suppressed under high glucose conditions. We showed that high glucose activates GSK3β but suppresses CXCR-4, β-catenin, LEF-1, and cyclin D1. Inhibition of GSK3β by LiCl led to increased levels of β-catenin, LEF-1, cyclin D1, and CXCR-4 expression. Our data indicate that GSK3β plays an important role in regulating the proliferation and migration of BMSCs by inhibiting cyclin D1 and CXCR-4 under high glucose conditions.

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References

  1. Selea A, Sumarac-Dumanović M, Pesić M, Suluburić D, Stamenković-Pejković D, Cvijović G, Micić D (2011) The effects of education with printed material on glycemic control in patients with diabetes type 2 treated with different therapeutic regimens. Vojnosanit Pregl 68:676–683

    Article  PubMed  Google Scholar 

  2. Wada K, Yu W, Elazizi M, Barakat S, Ouimet MA, Rosario-Meléndez R, Fiorellini JP, Graves DT, Uhrich KE (2013) Locally delivered salicylic acid from a poly(anhydride-ester): impact on diabetic bone regeneration. J Control Release 71:33–37

    Article  Google Scholar 

  3. Adami S (2009) Bone health in diabetes: considerations for clinical management. Curr Med Res Opin 25:1057–1072

    Article  PubMed  Google Scholar 

  4. Claes L, Recknagel S, Ignatius A (2012) Ignatius. Fracture healing under healthy and inflammatory conditions. Nat Rev Rheumatol 8:133–143

    Article  CAS  PubMed  Google Scholar 

  5. Roy B (2013) Biomolecular basis of the role of diabetes mellitus in osteoporosis and bone fractures. World J Diabetes 4:101–113

    Article  PubMed  PubMed Central  Google Scholar 

  6. Yamamoto M (2013) Secondary Osteoporosis or Secondary Contributors to Bone Loss in Fracture Bone metabolic disorders in patients with diabetes mellitus. Clin Calcium 23:1327–1335

    CAS  PubMed  Google Scholar 

  7. Caplan AI (1991) Mesenchymal stem cells. J Orthop Res 9:641–650

    Article  CAS  PubMed  Google Scholar 

  8. Zigdon-Giladi H, Lewinson D, Bick T, Machtei EE (2013) Mesenchymal stem cells combined with barrier domes enhance vertical bone formation. J Clin Periodontol 40:196–202

    Article  PubMed  Google Scholar 

  9. Kim SY, Lee JY, Park YD, Kang KL, Lee JC, Heo JS (2013) Hesperetin alleviates the inhibitory effects of high glucose on the osteoblastic differentiation of periodontal ligament stem cells. PLoS One 28:e67504

    Article  Google Scholar 

  10. Liu N, Shi S, Deng M, Tang L, Zhang G, Liu N, Ding B, Liu W, Liu Y, Shi H, Liu L, Jin Y (2011) High levels of β-catenin signaling reduce osteogenic differentiation of stem cells in inflammatory microenvironments through inhibition of the noncanonical Wnt pathway. J Bone Miner Res 26:2082–2095

    Article  CAS  PubMed  Google Scholar 

  11. Hawkins KE, Sharp TV, McKay TR (2011) The role of hypoxia in stem cell potency and differentiation. Regen Med 8:771–782

    Article  Google Scholar 

  12. Ma P, Xiong W, Liu H, Ma J, Gu B, Wu X (2011) Extrapancreatic roles of glimepiride on osteoblasts from rat manibular bone in vitro: regulation of cytodifferentiation through PI3-kinases/Akt signalling pathway. Arch Oral Biol 56:307–316

    Article  CAS  PubMed  Google Scholar 

  13. Song G, Habibovic P, BaoC HuJ, van Blitterswijk CA, Yuan H, Chen W, Xu HH (2013) The homing of bone marrow MSCs to non-osseous sites for ectopic bone formation induced by osteoinductive calcium phosphate. Biomaterials 34:2167–2176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wang X, Wang Y, Gou W, Lu Q, Peng J, Lu S (2013) Role of mesenchymal stem cells in bone regeneration and fracture repair: a review. Int Orthop 37:2491–2498

    Article  PubMed  PubMed Central  Google Scholar 

  15. Wynn RF, Hart CA, Corradi-Perini C, O’Neill L, Evans CA, Wraith JE, Fairbairn LJ, Bellantuono I (2004) A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow. Blood 104:2643–2645

    Article  CAS  PubMed  Google Scholar 

  16. Rombouts WJ, Ploemacher RE (2003) Primary murine MSC show highly efficient homing to the bone marrow but lose homing ability following culture. Leukemia 17:160–170

    Article  CAS  PubMed  Google Scholar 

  17. Granero-Moltó F, Weis JA, Miga MI, Landis B, Landis B, Myers TJ, O’Rear L, Longobardi L, Jansen ED, Mortlock DP, Spagnoli A (2009) Regenerative effects of transplanted mesenchymal stem cells in fracture healing. Stem Cell 27:1887–1898

    Article  Google Scholar 

  18. Cao J, Wang L, Du ZJ, Liu P, Zhang YB, Sui JF, Liu YP, Lei DL (2013) Recruitment of exogenous mesenchymal stem cells in mandibular distraction osteogenesis by the stromal cell-derived factor-1/chemokine receptor-4 pathway in rats. Br J Oral Maxillofac Surg 51:937–941

    Article  PubMed  Google Scholar 

  19. Kitaori T, Ito H, Schwarz EM, Tsutsumi R, Yoshitomi H, Oishi S, Nakano M, Fujii N, Nagasawa T, Nakamura T (2009) Stromal cell-derived factor 1/CXCR4 signaling is critical for the recruitment of mesenchymal stem cells to the fracture site during skeletal repair in a mouse model. Arthritis Rheum 60:813–823

    Article  CAS  PubMed  Google Scholar 

  20. Liu X, Zhou C, Li Y, Ji Y, Xu G, Wang X, Yan J (2013) SDF-1 promotes endochondral bone repair during fracture healing at the traumatic brain injury condition. PLoS One 8:e54077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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 24:1892–1903

    Article  CAS  PubMed  Google Scholar 

  22. Kockeritz L, Doble B, Patel S, Woodgett JR (2006) Glycogen synthase kinase-3–anoverview of an over-achieving protein kinase. Curr Drug Targets 7:1377–1388

    Article  CAS  PubMed  Google Scholar 

  23. Kong X, Liu Y, Ye R, Zhu B, Zhu Y, Liu X, Hu C, Luo H, Zhang Y, Ding Y, Jin Y (2013) GSK3β is a checkpoint for TNF-α-mediated impaired osteogenic differentiation of mesenchymal stem cells in inflammatory microenvironments. Biochim Biophys Acta 1830:5119–5129

    Article  CAS  PubMed  Google Scholar 

  24. Matsuda T, Zhai P, Maejima Y, Hong C, Gao S, Tian B, Goto K, Takagi H, Tamamori-Adachi M, Kitajima S, Sadoshima J (2008) Distinct roles of GSK-3alpha and GSK-3beta phosphorylation in the heart under pressure overload. Proc Natl Acad Sci USA 105:20900–20905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kim YS, Noh MY, Kim JY, Yu HJ, Kim KS, Kim SH, Koh SH (2013) Direct GSK-3β inhibition enhances mesenchymal stromal cell migration by increasing expression of β-PIX and CXCR4. Mol Neurobiol 47:811–820

    Article  CAS  PubMed  Google Scholar 

  26. Liu J, Han G, Liu H, Qin C (2008) Suppression of cholangiocarcinoma cell growth by human umbilical cord mesenchymal stem cells: a possible role of Wnt and Akt signaling. PLoS One 8:e62844

    Article  Google Scholar 

  27. Shtutman M, Zhurinsky J, Simcha I, Albanese C, D’Amico M, Pestell R, Ben-Ze’ev A (1999) The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci USA 96:5522–5527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G (1993) Cyclin D1 is a nuclearprotein required for cell cycle progression in G1. Genes Dev 7:812–821

    Article  CAS  PubMed  Google Scholar 

  29. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Dj Prockop, Horwitz E (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317

    Article  CAS  PubMed  Google Scholar 

  30. Kern S, Eichler H, Stoeve J, Klüter H, Bieback K (2006) Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 24:1294–1301

    Article  CAS  PubMed  Google Scholar 

  31. Rojewski MT, Weber BM, Phenotypic Schrezenmeier H (2008) Characterization of mesenchymal stem cells from various tissues. Transfus Med Hemother 35:168–184

    Article  PubMed  PubMed Central  Google Scholar 

  32. Fukumoto S, Nishizawa Y, Koyama H, Yamakawa K, Ohno S, Morii H (1997) Protein kinase C delta inhibits the proliferation of vascular smooth muscle cells by suppressing G1 cyclin expression. J Biol Chem 272:13816–13822

    Article  CAS  PubMed  Google Scholar 

  33. Fukumoto S, Koyama H, Hosoi M, Yamakawa K, Tanaka S, Morii H, Nishizawa Y (1999) Distinct role of cAMP and cGMP in the cell cycle control of vascular smooth muscle cells: cGMP delays cell cycle transition through suppression of cyclin D1 and cyclin-dependent kinase 4 activation. Circ Res 85:985–991

    Article  CAS  PubMed  Google Scholar 

  34. Kluk MJ, Hla T (2001) Role of the sphingosine 1-phosphate receptor EDG-1 in vascular smooth muscle cell proliferation and migration. Circ Res 89:496–502

    Article  CAS  PubMed  Google Scholar 

  35. Ishigami M, Swertfeger DK, Granholm NA, Hui DY (1998) Apolipoprotein E inhibits platelet-derived growth factor-induced vascular smooth muscle cell migration and proliferation by suppressing signal transduction and preventing cell entry to G1 phase. J Biol Chem 273:20156–20161

    Article  CAS  PubMed  Google Scholar 

  36. Moon RT, Bowerman B, Boutros M, Perrimon N (2002) The promise and perils of Wnt signaling through beta-catenin. Science 296:1644–1646

    Article  CAS  PubMed  Google Scholar 

  37. Novak A (1999) Dedhar S. Signaling through beta-catenin and Lef/Tcf. Cell Mol Life Sci 56:523–537

    Article  CAS  PubMed  Google Scholar 

  38. Porfiri E, Rubinfeld B, Albert I, Hovanes K, Waterman M, Polakis P (1997) Induction of a beta-catenin-LEF-1 complex by wnt-1 and transforming mutants of beta-catenin. Oncogene 15:2833–2839

    Article  CAS  PubMed  Google Scholar 

  39. Koehler A, Schlupf J, Schneider M, Kraft B, Winter C, Kashef J (2013) Loss of Xenopus cadherin-11 leads to increased Wnt/β-catenin signaling and up-regulation of target genes c-myc and cyclin D1 in neural crest. Dev Biol 383:132–145

    Article  CAS  PubMed  Google Scholar 

  40. Gopalakrishnan V, Vignesh RC, Arunakaran J, Aruldhas MM, Srinivasan N (2006) Effects of glucose and its modulation by insulin and estradiol on BMSC differentiation into osteoblastic lineages. Biochem Cell Biol 84:93–101

    Article  CAS  PubMed  Google Scholar 

  41. Abbott J, Huang Y, Liu D, Hickey R, Krause DS, Giordano FJ (2004) Stromal cell-derived factor-1 alpha plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury. Circulation 110:3300–3305

    Article  PubMed  Google Scholar 

  42. Ji J, He B, Dheen S, Tay S (2004) Interactions of chemokines and chemokine receptors mediate the migration of mesenchymal stem cells to the impaired site in the brain after hypoglossal nerve injury. Stem Cells 22:415–427

    Article  CAS  PubMed  Google Scholar 

  43. Ceradini D, Kulkarni A, Callaghan M, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10:858–864

    Article  CAS  PubMed  Google Scholar 

  44. Chang G, Zhang H, Wang J, Zhang Y, Xu H, Wang C, Zhang H, Ma L, Li Q, Pang T (2013) CD44 targets Wnt/β-catenin pathway to mediate the proliferation of K562 cells. Cancer Cell Int 13:117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Cho J, Rameshwar P, Sadoshima J (2009) Distinct roles of glycogen synthase kinase (GSK)-3alpha and GSK-3beta in mediating cardiomyocyte differentiation in murine bone marrow-derived mesenchymal stem cells. J Biol Chem 284:36647–36658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Gagliardi M, Hernandez A, McGough IJ, Vincent JP (2014) Inhibitors of endocytosis prevent Wnt/Wingless signalling by reducing the level of basal β-catenin/Armadillo. J Cell Sci 127:4918–4926

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We thank Wei Zhang for help with the biochemical analyses and Man Wu for critically reading and editing the manuscript. This work was supported by the Natural Science Foundation of China (81271180, 31200741, 81070833 and 51003114), the China Postdoctoral Science Foundation (2013M532108), and the Beijing Nova program (Z14111000180000).

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All the authors state that they have no conflicts of interest.

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    Authors and Affiliations

    1. Stomatology Department, General Hospital of Chinese PLA, 28 FuXing Road, Beijing, 100853, China

      Bo Zhang, Na Liu, Hao Wu, Yuxuan Gao, Huixia He, Bin Gu & Hongchen Liu

    2. Technical Institute of Physics and Chemistry of CAS, Beijing, China

      Haigang Shi

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    1. Bo Zhang
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    Correspondence to Bin Gu or Hongchen Liu.

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    As the co-first author, B. Zhang and N. Liu contributed equally to this work.

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    Zhang, B., Liu, N., Shi, H. et al. High glucose microenvironments inhibit the proliferation and migration of bone mesenchymal stem cells by activating GSK3β. J Bone Miner Metab 34, 140–150 (2016). https://doi.org/10.1007/s00774-015-0662-6

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    • DOI: https://doi.org/10.1007/s00774-015-0662-6

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