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Current Molecular Biology Reports

, Volume 3, Issue 2, pp 107–113 | Cite as

Reciprocal Regulation of PPARγ and RUNX2 Activities in Marrow Mesenchymal Stem Cells: Fine Balance between p38 MAPK and Protein Phosphatase 5

  • Lance A. Stechschulte
  • Beata Lecka-CzernikEmail author
Molecular Biology of Skeletal Development (T Bellido, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Molecular Biology of Skeletal Development

Abstract

Purpose of Review

Post-translational modifications (PTMs), specifically serine phosphorylation, are essential for determination and tuning up an activity of many proteins, including those that are involved in the control of gene transcription. Transcription factors PPARγ2 and RUNX2 are essential for mesenchymal stem cell (MSC) commitment to either adipocyte or osteoblast lineage. This review is summarizing current knowledge how serine phosphorylation PTMs regulate activities of both transcription factors and MSCs lineage commitment.

Recent Findings

Both PPARγ2 and RUNX2 transcriptional activities are regulated by similar PTMs, however with an opposite outcome. The same p38 MAPK mediates serine phosphorylation that leads to activation of RUNX2 and inactivation of PPARγ2. The process of protein phosphorylation is balanced with a process of protein dephosphorylation. Protein phosphatase 5 simultaneously dephosphorylates both proteins, which results in activation of PPARγ2 and inactivation of RUNX2.

Summary

This review provides a summary of the “yin yang” fine-tuned mechanism by which p38 MAPK and PP5 regulate MSCs lineage commitment.

Keywords

Osteoblasts Adipocytes p38 MAPK PP5 RUNX2 PPARγ2 Bone Rosiglitazone 

Notes

Acknowledgements

This work was supported by the American Diabetes Association (ADA) grant no.1-17-PDF-067 to LAS and grants from NIH DK105825 and ADA 7-13-BS-089 to BLC.

Compliance with Ethical Standards

Conflict of Interest

Lance A. Stechschulte and Beata Lecka-Czernik declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance•• Of major importance

  1. 1.
    Madras N, Gibbs AL, Zhou Y, Zandstra PW, Aubin JE. Modeling stem cell development by retrospective analysis of gene expression profiles in single progenitor-derived colonies. Stem Cells. 2002;20(3):230–40.CrossRefPubMedGoogle Scholar
  2. 2.
    • Bianco P, Robey PG. Skeletal stem cells. Development. 2015;142(6):1023–7. doi: 10.1242/dev.102210. This ia a comprehensive review of skeletal stem cell biology and potential therapeutic uses.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Shockley KR, Lazarenko OP, Czernik PJ, Rosen CJ, Churchill GA, Lecka-Czernik B. PPARgamma2 nuclear receptor controls multiple regulatory pathways of osteoblast differentiation from marrow mesenchymal stem cells. J Cell Biochem. 2009;106(2):232–46. doi: 10.1002/jcb.21994.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Rahman S, Czernik PJ, Lu Y, Lecka-Czernik B. Beta-catenin directly sequesters adipocytic and insulin sensitizing activities but not osteoblastic activity of PPARgamma2 in marrow mesenchymal stem cells. PLoS One. 2012;7(12):e51746.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Hong JH, Hwang ES, McManus MT, Amsterdam A, Tian Y, Kalmukova R, et al. TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science. 2005;309(5737):1074–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Lecka-Czernik B, Gubrij I, Moerman EJ, Kajkenova O, Lipschitz DA, Manolagas SC, et al. Inhibition of Osf2/Cbfa1 expression and terminal osteoblast differentiation by PPARgamma2. J Cell Biochem. 1999;74(3):357–71.CrossRefPubMedGoogle Scholar
  7. 7.
    • Shockley KR, Rosen CJ, Churchill GA, Lecka-Czernik B. PPARgamma2 regulates a molecular signature of marrow mesenchymal stem cells. PPAR Res. 2007;2007:81219. doi: 10.1155/2007/81219. This analysis demonstrates that MSCs “stemness” is under control of PPARγ2 protein.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Cohen P. The regulation of protein function by multisite phosphorylation--a 25 year update. Trends Biochem Sci. 2000;25(12):596–601.CrossRefPubMedGoogle Scholar
  9. 9.
    Cohen P. Protein phosphorylation and hormone action. Proceedings of the Royal Society of London Series B, Biological sciences. 1988;234(1275):115–44.CrossRefPubMedGoogle Scholar
  10. 10.
    Pearlman SM, Serber Z, Ferrell Jr JE. A mechanism for the evolution of phosphorylation sites. Cell. 2011;147(4):934–46. doi: 10.1016/j.cell.2011.08.052.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Adams M, Reginato MJ, Shao D, Lazar MA, Chatterjee VK. Transcriptional activation by peroxisome proliferator-activated receptor gamma is inhibited by phosphorylation at a consensus mitogen-activated protein kinase site. J Biol Chem. 1997;272(8):5128–32.CrossRefPubMedGoogle Scholar
  12. 12.
    Hu E, Kim JB, Sarraf P, Spiegelman BM. Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARgamma. Science. 1996;274(5295):2100–3.CrossRefPubMedGoogle Scholar
  13. 13.
    Hinds Jr TD, Stechschulte LA, Cash HA, Whisler D, Banerjee A, Yong W, et al. Protein phosphatase 5 mediates lipid metabolism through reciprocal control of glucocorticoid receptor and peroxisome proliferator-activated receptor-gamma (PPARgamma). J Biol Chem. 2011;286(50):42911–22. doi: 10.1074/jbc.M111.311662.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hosooka T, Noguchi T, Kotani K, Nakamura T, Sakaue H, Inoue H, et al. Dok1 mediates high-fat diet-induced adipocyte hypertrophy and obesity through modulation of PPAR-gamma phosphorylation. Nat Med. 2008;14(2):188–93.CrossRefPubMedGoogle Scholar
  15. 15.
    •• Stechschulte LA, Ge C, Hinds Jr TD, Sanchez ER, Franceschi RT, Lecka-Czernik B. Protein phosphatase PP5 controls bone mass and the negative effects of rosiglitazone on bone through reciprocal regulation of PPARgamma (peroxisome proliferator-activated receptor gamma) and RUNX2 (runt-related transcription factor 2). J Biol Chem. 2016;291(47):24475–86. doi: 10.1074/jbc.M116.752493. This study demonstrates that PP5 reciprocally regulates activities of PPARγ and RUNX2 and MSCs lineage commitment, and that PP5 deficiency protects bone entirely from the rosiglitazone-induced bone loss.CrossRefPubMedGoogle Scholar
  16. 16.
    •• Stechschulte LA, Czernik PJ, Rotter ZC, Tausif FN, Corzo CA, Marciano DP, et al. PPARG post-translational modifications regulate bone formation and bone resorption. EBioMedicine. 2016;10:174–84. doi: 10.1016/j.ebiom.2016.06.040. This study demonstrates for the first time that the same PPARγ PTM (S273) which regulates insulin sensitivity also regulates osteoclast differentiation independently from S112 which regulates adipocyte differentiation from MSCs.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Choi JH, Banks AS, Kamenecka TM, Busby SA, Chalmers MJ, Kumar N, et al. Antidiabetic actions of a non-agonist PPARgamma ligand blocking Cdk5-mediated phosphorylation. Nature. 2011;477(7365):477–81.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Dhavan R, Tsai LH. A decade of CDK5. Nat Rev Mol Cell Biol. 2001;2(10):749–59. doi: 10.1038/35096019.CrossRefPubMedGoogle Scholar
  19. 19.
    Kusakawa G, Saito T, Onuki R, Ishiguro K, Kishimoto T, Hisanaga S. Calpain-dependent proteolytic cleavage of the p35 cyclin-dependent kinase 5 activator to p25. J Biol Chem. 2000;275(22):17166–72. doi: 10.1074/jbc.M907757199.CrossRefPubMedGoogle Scholar
  20. 20.
    Utreras E, Futatsugi A, Rudrabhatla P, Keller J, Iadarola MJ, Pant HC, et al. Tumor necrosis factor-alpha regulates cyclin-dependent kinase 5 activity during pain signaling through transcriptional activation of p35. J Biol Chem. 2009;284(4):2275–84. doi: 10.1074/jbc.M805052200.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Ferron M, Wei J, Yoshizawa T, Del Fattore A, Depinho RA, Teti A, et al. Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell. 2010;142(2):296–308.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Wee HJ, Huang G, Shigesada K, Ito Y. Serine phosphorylation of RUNX2 with novel potential functions as negative regulatory mechanisms. EMBO Rep. 2002;3(10):967–74. doi: 10.1093/embo-reports/kvf193.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Huang G, Shigesada K, Ito K, Wee HJ, Yokomizo T, Ito Y. Dimerization with PEBP2beta protects RUNX1/AML1 from ubiquitin-proteasome-mediated degradation. EMBO J. 2001;20(4):723–33. doi: 10.1093/emboj/20.4.723.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Kugimiya F, Kawaguchi H, Ohba S, Kawamura N, Hirata M, Chikuda H, et al. GSK-3beta controls osteogenesis through regulating Runx2 activity. PLoS One. 2007;2(9):e837. doi: 10.1371/journal.pone.0000837.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Zaidi SK, Sullivan AJ, Medina R, Ito Y, van Wijnen AJ, Stein JL, et al. Tyrosine phosphorylation controls Runx2-mediated subnuclear targeting of YAP to repress transcription. EMBO J. 2004;23(4):790–9.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Ge C, Xiao G, Jiang D, Yang Q, Hatch NE, Roca H, et al. Identification and functional characterization of ERK/MAPK phosphorylation sites in the Runx2 transcription factor. J Biol Chem. 2009;284(47):32533–43. doi: 10.1074/jbc.M109.040980.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Greenblatt MB, Shim JH, Zou W, Sitara D, Schweitzer M, Hu D, et al. The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice. J Clin Invest. 2010;120(7):2457–73. doi: 10.1172/JCI42285.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Zou W, Greenblatt MB, Shim JH, Kant S, Zhai B, Lotinun S, et al. MLK3 regulates bone development downstream of the faciogenital dysplasia protein FGD1 in mice. J Clin Invest. 2011;121(11):4383–92. doi: 10.1172/JCI59041.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Cuadrado A, Nebreda AR. Mechanisms and functions of p38 MAPK signalling. Biochem J. 2010;429(3):403–17. doi: 10.1042/BJ20100323.CrossRefPubMedGoogle Scholar
  30. 30.
    Rodriguez-Carballo E, Gamez B, Ventura F. p38 MAPK signaling in osteoblast differentiation. Front Cell Dev Biol. 2016;4:40. doi: 10.3389/fcell.2016.00040.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Wang XZ, Ron D. Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP kinase. Science. 1996;272(5266):1347–9.CrossRefPubMedGoogle Scholar
  32. 32.
    Yang TT, Xiong Q, Enslen H, Davis RJ, Chow CW. Phosphorylation of NFATc4 by p38 mitogen-activated protein kinases. Mol Cell Biol. 2002;22(11):3892–904.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Yan J, Gan L, Chen D, Sun C. Adiponectin impairs chicken preadipocytes differentiation through p38 MAPK/ATF-2 and TOR/p70 S6 kinase pathways. PLoS One. 2013;8(10):e77716. doi: 10.1371/journal.pone.0077716.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Aouadi M, Laurent K, Prot M, Le Marchand-Brustel Y, Binetruy B, Bost F. Inhibition of p38MAPK increases adipogenesis from embryonic to adult stages. Diabetes. 2006;55(2):281–9.CrossRefPubMedGoogle Scholar
  35. 35.
    Feng M, Tian L, Gan L, Liu Z, Sun C. Mark4 promotes adipogenesis and triggers apoptosis in 3T3-L1 adipocytes by activating JNK1 and inhibiting p38MAPK pathways. Biol Cell. 2014;106(9):294–307. doi: 10.1111/boc.201400004.CrossRefPubMedGoogle Scholar
  36. 36.
    Jaiswal RK, Jaiswal N, Bruder SP, Mbalaviele G, Marshak DR, Pittenger MF. Adult human mesenchymal stem cell differentiation to the osteogenic or adipogenic lineage is regulated by mitogen-activated protein kinase. J Biol Chem. 2000;275(13):9645–52.CrossRefPubMedGoogle Scholar
  37. 37.
    Gallea S, Lallemand F, Atfi A, Rawadi G, Ramez V, Spinella-Jaegle S, et al. Activation of mitogen-activated protein kinase cascades is involved in regulation of bone morphogenetic protein-2-induced osteoblast differentiation in pluripotent C2C12 cells. Bone. 2001;28(5):491–8.CrossRefPubMedGoogle Scholar
  38. 38.
    Suzuki A, Guicheux J, Palmer G, Miura Y, Oiso Y, Bonjour JP, et al. Evidence for a role of p38 MAP kinase in expression of alkaline phosphatase during osteoblastic cell differentiation. Bone. 2002;30(1):91–8.CrossRefPubMedGoogle Scholar
  39. 39.
    Suzuki A, Palmer G, Bonjour JP, Caverzasio J. Regulation of alkaline phosphatase activity by p38 MAP kinase in response to activation of Gi protein-coupled receptors by epinephrine in osteoblast-like cells. Endocrinology. 1999;140(7):3177–82. doi: 10.1210/endo.140.7.6857.CrossRefPubMedGoogle Scholar
  40. 40.
    Thouverey C, Caverzasio J. Focus on the p38 MAPK signaling pathway in bone development and maintenance. Bonekey Rep. 2015;4:711. doi: 10.1038/bonekey.2015.80.PubMedPubMedCentralGoogle Scholar
  41. 41.
    •• Ge C, Cawthorn WP, Li Y, Zhao G, MacDougald OA, Franceschi RT. Reciprocal control of osteogenic and adipogenic differentiation by ERK/MAP kinase phosphorylation of Runx2 and PPARgamma transcription factors. J Cell Physiol. 2016;231(3):587–96. doi: 10.1002/jcp.25102. This study demonstrates for the first time that PPARγ and RUNX2 activities are regulated by the same MAPKs.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Chinkers M. Targeting of a distinctive protein-serine phosphatase to the protein kinase-like domain of the atrial natriuretic peptide receptor. Proc Natl Acad Sci U S A. 1994;91(23):11075–9.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Chen MX, McPartlin AE, Brown L, Chen YH, Barker HM, Cohen PT. A novel human protein serine/threonine phosphatase, which possesses four tetratricopeptide repeat motifs and localizes to the nucleus. EMBO J. 1994;13(18):4278–90.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Becker W, Kentrup H, Klumpp S, Schultz JE, Joost HG. Molecular cloning of a protein serine/threonine phosphatase containing a putative regulatory tetratricopeptide repeat domain. J Biol Chem. 1994;269(36):22586–92.PubMedGoogle Scholar
  45. 45.
    Chen MX, Cohen PT. Activation of protein phosphatase 5 by limited proteolysis or the binding of polyunsaturated fatty acids to the TPR domain. FEBS Lett. 1997;400(1):136–40.CrossRefPubMedGoogle Scholar
  46. 46.
    Hinds Jr TD, Sanchez ER. Protein phosphatase 5. Int J Biochem Cell Biol. 2008;40(11):2358–62. doi: 10.1016/j.biocel.2007.08.010.CrossRefPubMedGoogle Scholar
  47. 47.
    Kang H, Sayner SL, Gross KL, Russell LC, Chinkers M. Identification of amino acids in the tetratricopeptide repeat and C-terminal domains of protein phosphatase 5 involved in autoinhibition and lipid activation. Biochemistry. 2001;40(35):10485–90.CrossRefPubMedGoogle Scholar
  48. 48.
    Ramsey AJ, Chinkers M. Identification of potential physiological activators of protein phosphatase 5. Biochemistry. 2002;41(17):5625–32.CrossRefPubMedGoogle Scholar
  49. 49.
    Russell LC, Whitt SR, Chen MS, Chinkers M. Identification of conserved residues required for the binding of a tetratricopeptide repeat domain to heat shock protein 90. J Biol Chem. 1999;274(29):20060–3.CrossRefPubMedGoogle Scholar
  50. 50.
    Yang J, Roe SM, Cliff MJ, Williams MA, Ladbury JE, Cohen PT, et al. Molecular basis for TPR domain-mediated regulation of protein phosphatase 5. EMBO J. 2005;24(1):1–10. doi: 10.1038/sj.emboj.7600496.CrossRefPubMedGoogle Scholar
  51. 51.
    Dougherty MK, Muller J, Ritt DA, Zhou M, Zhou XZ, Copeland TD, et al. Regulation of Raf-1 by direct feedback phosphorylation. Mol Cell. 2005;17(2):215–24. doi: 10.1016/j.molcel.2004.11.055.CrossRefPubMedGoogle Scholar
  52. 52.
    Zuo Z, Dean NM, Honkanen RE. Serine/threonine protein phosphatase type 5 acts upstream of p53 to regulate the induction of p21(WAF1/Cip1) and mediate growth arrest. J Biol Chem. 1998;273(20):12250–8.CrossRefPubMedGoogle Scholar
  53. 53.
    Chinkers M. Protein phosphatase 5 in signal transduction. Trends Endocrinol Metab. 2001;12(1):28–32.CrossRefPubMedGoogle Scholar
  54. 54.
    Ollendorff V, Donoghue DJ. The serine/threonine phosphatase PP5 interacts with CDC16 and CDC27, two tetratricopeptide repeat-containing subunits of the anaphase-promoting complex. J Biol Chem. 1997;272(51):32011–8.CrossRefPubMedGoogle Scholar
  55. 55.
    Yong W, Bao S, Chen H, Li D, Sanchez ER, Shou W. Mice lacking protein phosphatase 5 are defective in ataxia telangiectasia mutated (ATM)-mediated cell cycle arrest. J Biol Chem. 2007;282(20):14690–4. doi: 10.1074/jbc.C700019200.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Ikeda K, Ogawa S, Tsukui T, Horie-Inoue K, Ouchi Y, Kato S, et al. Protein phosphatase 5 is a negative regulator of estrogen receptor-mediated transcription. Mol Endocrinol. 2004;18(5):1131–43. doi: 10.1210/me.2003-0308.CrossRefPubMedGoogle Scholar
  57. 57.
    Chen MS, Silverstein AM, Pratt WB, Chinkers M. The tetratricopeptide repeat domain of protein phosphatase 5 mediates binding to glucocorticoid receptor heterocomplexes and acts as a dominant negative mutant. J Biol Chem. 1996;271(50):32315–20.CrossRefPubMedGoogle Scholar
  58. 58.
    Rzonca SO, Suva LJ, Gaddy D, Montague DC, Lecka-Czernik B. Bone is a target for the antidiabetic compound rosiglitazone. Endocrinology. 2004;145(1):401–6.CrossRefPubMedGoogle Scholar
  59. 59.
    Lazarenko OP, Rzonca SO, Hogue WR, Swain FL, Suva LJ, Lecka-Czernik B. Rosiglitazone induces decreases in bone mass and strength that are reminiscent of aged bone. Endocrinology. 2007;148(6):2669–80. doi: 10.1210/en.2006-1587.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Schwartz AV. TZDs and bone: a review of the recent clinical evidence. PPAR Res. 2008;2008:297893.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Zinman B, Haffner SM, Herman WH, Holman RR, Lachin JM, Kravitz BG, et al. Effect of rosiglitazone, metformin, and glyburide on bone biomarkers in patients with type 2 diabetes. J Clin Endocrinol Metab. 2010;95(1):134–42. doi: 10.1210/jc.2009-0572.CrossRefPubMedGoogle Scholar
  62. 62.
    • Schwartz AV, Chen H, Ambrosius WT, Sood A, Josse RG, Bonds DE, et al. Effects of TZD use and discontinuation on fracture rates in ACCORD bone study. J Clin Endocrinol Metab. 2015;100(11):4059–66. doi: 10.1210/jc.2015-1215. This review summarizes the effect of anti-diabetic thiazolidinediones on bone loss and fracture risk in humans.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Lance A. Stechschulte
    • 1
    • 3
  • Beata Lecka-Czernik
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of Orthopaedic SurgeryUniversity of Toledo Health Sciences CampusToledoUSA
  2. 2.Physiology and PharmacologyUniversity of Toledo Health Sciences CampusToledoUSA
  3. 3.Center for Diabetes and Endocrine DiseasesUniversity of Toledo Health Sciences CampusToledoUSA

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