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p38-MAPK signaling pathway is not involved in osteogenic differentiation during early response of mesenchymal stem cells to continuous mechanical strain

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Abstract

Mechanical stimuli play a significant role in the regulation of bone remodeling during orthodontic tooth movement. However, the correlation between mechanical strain and bone remodeling is still poorly understood. In this study, we used a model of continuous mechanical strain (CMS) on bone mesenchymal stem cells (BMSCs) to investigate the proliferation and osteogenic differentiation of BMSCs and the mechanism of mechano-transduction. A CMS of 10 % at 1 Hz suppressed the proliferation of BMSCs and induced early osteogenic differentiation within 48 h by activating Runx2 and increasing alkaline phosphatase (ALP) activity and mRNA expression of osteogenesis-related genes (ALP, collagen type I, and osteopontin). Regarding mitogen-activated protein kinase (MAPK) activation, CMS induced phased phosphorylation of p38 consisting of a rapid induction of p38 MAPK at 10 min and a rapid decay after 1 h. Furthermore, the potent p38 inhibitor SB203580 blocked the induction of p38 MAPK signaling, but had little effect on subsequent osteogenic events. These results demonstrate that mechanical strain may act as a stimulator to induce the differentiation of BMSCs into osteoblasts, which is a vital function for bone formation in orthodontic tooth movement. However, activation of the p38 signaling pathway may not be involved in this process.

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References

  1. Duncan RL, Turner CH (1995) Mechanotransduction and the functional response of bone to mechanical strain. Calcif Tissue Int 57:344–358

    Article  PubMed  CAS  Google Scholar 

  2. Umemura Y, Baylink DJ, Wergedal JE, Mohan S, Srivastava AK (2002) A time course of bone response to jump exercise in C57BL/6J mice. J Bone Miner Metab 20:209–215

    Article  PubMed  Google Scholar 

  3. Henneman S, Von den Hoff JW, Maltha JC (2008) Mechanobiology of tooth movement. Eur J Orthod 30:299–306

    Article  PubMed  CAS  Google Scholar 

  4. Beck BR, Kent K, Holloway L, Marcus R (2006) Novel, high-frequency, low-strain mechanical loading for premenopausal women with low bone mass: early findings. J Bone Miner Metab 24:505–507

    Article  PubMed  Google Scholar 

  5. Donahue SW, Jacobs CR, Donahue HJ (2001) Flow-induced calcium oscillations in rat osteoblasts are age, loading frequency, and shear stress dependent. Am J Physiol Cell Physiol 281:C1635–C1641

    PubMed  CAS  Google Scholar 

  6. Rath B, Nam J, Knobloch TJ, Lannutti JJ, Agarwal S (2008) Compressive forces induce osteogenic gene expression in calvarial osteoblasts. J Biomech 41:1095–1103

    Article  PubMed  Google Scholar 

  7. Suzuki N, Yoshimura Y, Deyama Y, Suzuki K, Kitagawa Y (2008) Mechanical stress directly suppresses osteoclast differentiation in RAW264.7 cells. Int J Mol Med 21:291–296

    PubMed  CAS  Google Scholar 

  8. Costessi A, Pines A, D’Andrea P et al (2005) Extracellular nucleotides activate Runx2 in the osteoblast-like HOBIT cell line: a possible molecular link between mechanical stress and osteoblasts’ response. Bone 36:418–432

    Article  PubMed  CAS  Google Scholar 

  9. Huiskes R, Ruimerman R, van Lenthe GH, Janssen JD (2000) Effects of mechanical forces on maintenance and adaptation of form in trabecular bone. Nature 405:704–706

    Article  PubMed  CAS  Google Scholar 

  10. Chao EY, Inoue N (2003) Biophysical stimulation of bone fracture repair, regeneration and remodelling. Eur Cell Mater 6:72–84 discussion 84–75

    PubMed  Google Scholar 

  11. Thorpe SD, Buckley CT, Vinardell T, O’Brien FJ, Campbell VA, Kelly DJ (2010) The response of bone marrow-derived mesenchymal stem cells to dynamic compression following TGF-beta3 induced chondrogenic differentiation. Ann Biomed Eng 38:2896–2909

    Article  PubMed  Google Scholar 

  12. Li H, Marijanovic I, Kronenberg MS et al (2008) Expression and function of Dlx genes in the osteoblast lineage. Dev Biol 316:458–470

    Article  PubMed  CAS  Google Scholar 

  13. Karsenty G, Ducy P, Starbuck M et al (1999) Cbfa1 as a regulator of osteoblast differentiation and function. Bone 25:107–108

    Article  PubMed  CAS  Google Scholar 

  14. Nakashima K, Zhou X, Kunkel G et al (2002) The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108:17–29

    Article  PubMed  CAS  Google Scholar 

  15. Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G (1997) Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89:747–754

    Article  PubMed  CAS  Google Scholar 

  16. Mundlos S, Otto F, Mundlos C et al (1997) Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 89:773–779

    Article  PubMed  CAS  Google Scholar 

  17. Ahdjoudj S, Lasmoles F, Holy X, Zerath E, Marie PJ (2002) Transforming growth factor beta2 inhibits adipocyte differentiation induced by skeletal unloading in rat bone marrow stroma. J Bone Miner Res 17:668–677

    Article  PubMed  CAS  Google Scholar 

  18. Arnsdorf EJ, Tummala P, Kwon RY, Jacobs CR (2009) Mechanically induced osteogenic differentiation—the role of RhoA, ROCKII and cytoskeletal dynamics. J Cell Sci 122:546–553

    Article  PubMed  CAS  Google Scholar 

  19. Hie M, Tsukamoto I (2010) Increased expression of the receptor for activation of NF-kappaB and decreased runt-related transcription factor 2 expression in bone of rats with streptozotocin-induced diabetes. Int J Mol Med 26:611–618

    PubMed  CAS  Google Scholar 

  20. Ziros PG, Gil AP, Georgakopoulos T et al (2002) The bone-specific transcriptional regulator Cbfa1 is a target of mechanical signals in osteoblastic cells. J Biol Chem 277:23934–23941

    Article  PubMed  CAS  Google Scholar 

  21. Johnson GL, Lapadat R (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298:1911–1912

    Article  PubMed  CAS  Google Scholar 

  22. Matsuda N, Morita N, Matsuda K, Watanabe M (1998) Proliferation and differentiation of human osteoblastic cells associated with differential activation of MAP kinases in response to epidermal growth factor, hypoxia, and mechanical stress in vitro. Biochem Biophys Res Commun 249:350–354

    Article  PubMed  CAS  Google Scholar 

  23. Lai CF, Cheng SL (2002) Signal transductions induced by bone morphogenetic protein-2 and transforming growth factor-beta in normal human osteoblastic cells. J Biol Chem 277:15514–15522

    Article  PubMed  CAS  Google Scholar 

  24. Rubin J, Rubin C, Jacobs CR (2006) Molecular pathways mediating mechanical signaling in bone. Gene 367:1–16

    Article  PubMed  CAS  Google Scholar 

  25. Kawarizadeh A, Bourauel C, Gotz W, Jager A (2005) Early responses of periodontal ligament cells to mechanical stimulus in vivo. J Dent Res 84:902–906

    Article  PubMed  CAS  Google Scholar 

  26. Liedert A, Kaspar D, Blakytny R, Claes L, Ignatius A (2006) Signal transduction pathways involved in mechanotransduction in bone cells. Biochem Biophys Res Commun 349:1–5

    Article  PubMed  CAS  Google Scholar 

  27. Maniatopoulos C, Sodek J, Melcher AH (1988) Bone formation in vitro by stromal cells obtained from bone marrow of young adult rats. Cell Tissue Res 254:317–330

    Article  PubMed  CAS  Google Scholar 

  28. Umemura Y, Nagasawa S, Honda A, Singh R (2008) High-impact exercise frequency per week or day for osteogenic response in rats. J Bone Miner Metab 26:456–460

    Article  PubMed  Google Scholar 

  29. Franceschi RT, Xiao G, Jiang D, Gopalakrishnan R, Yang S, Reith E (2003) Multiple signaling pathways converge on the Cbfa1/Runx2 transcription factor to regulate osteoblast differentiation. Connect Tissue Res 44(Suppl 1):109–116

    PubMed  CAS  Google Scholar 

  30. Melsen B (2001) Tissue reaction to orthodontic tooth movement—a new paradigm. Eur J Orthod 23:671–681

    Article  PubMed  CAS  Google Scholar 

  31. Kaspar D, Seidl W, Neidlinger-Wilke C, Beck A, Claes L, Ignatius A (2002) Proliferation of human-derived osteoblast-like cells depends on the cycle number and frequency of uniaxial strain. J Biomech 35:873–880

    Article  PubMed  Google Scholar 

  32. McGuinness NJ, Wilson AN, Jones ML, Middleton J (1991) A stress analysis of the periodontal ligament under various orthodontic loadings. Eur J Orthod 13:231–242

    Article  PubMed  CAS  Google Scholar 

  33. Jagodzinski M, Breitbart A, Wehmeier M et al (2008) Influence of perfusion and cyclic compression on proliferation and differentiation of bone marrow stromal cells in 3-dimensional culture. J Biomech 41:1885–1891

    Article  PubMed  CAS  Google Scholar 

  34. Riddle RC, Taylor AF, Genetos DC, Donahue HJ (2006) MAP kinase and calcium signaling mediate fluid flow-induced human mesenchymal stem cell proliferation. Am J Physiol Cell Physiol 290:C776–C784

    Article  PubMed  CAS  Google Scholar 

  35. Song G, Ju Y, Shen X, Luo Q, Shi Y, Qin J (2007) Mechanical stretch promotes proliferation of rat bone marrow mesenchymal stem cells. Colloids Surf B Biointerfaces 58:271–277

    Article  PubMed  CAS  Google Scholar 

  36. Caetano-Lopes J, Canhao H, Fonseca JE (2007) Osteoblasts and bone formation. Acta Reumatol Port 32:103–110

    PubMed  Google Scholar 

  37. Yoshikawa T, Peel SA, Gladstone JR, Davies JE (1997) Biochemical analysis of the response in rat bone marrow cell cultures to mechanical stimulation. Biomed Mater Eng 7:369–377

    PubMed  CAS  Google Scholar 

  38. Jagodzinski M, Drescher M, Zeichen J et al (2004) Effects of cyclic longitudinal mechanical strain and dexamethasone on osteogenic differentiation of human bone marrow stromal cells. Eur Cell Mater 7:35–41 discussion 41

    PubMed  CAS  Google Scholar 

  39. Wozniak M, Fausto A, Carron CP, Meyer DM, Hruska KA (2000) Mechanically strained cells of the osteoblast lineage organize their extracellular matrix through unique sites of alphavbeta3-integrin expression. J Bone Miner Res 15:1731–1745

    Article  PubMed  CAS  Google Scholar 

  40. Eriksen EF (2010) Cellular mechanisms of bone remodeling. Rev Endocr Metabol Disord 11:219–227

    Article  Google Scholar 

  41. Nakashima K, de Crombrugghe B (2003) Transcriptional mechanisms in osteoblast differentiation and bone formation. Trends Genet 19:458–466

    Article  PubMed  CAS  Google Scholar 

  42. Fan X, Rahnert JA, Murphy TC, Nanes MS, Greenfield EM, Rubin J (2006) Response to mechanical strain in an immortalized pre-osteoblast cell is dependent on ERK1/2. J Cell Physiol 207:454–460

    Article  PubMed  CAS  Google Scholar 

  43. Suzuki A, Guicheux J, Palmer G et al (2002) Evidence for a role of p38 MAP kinase in expression of alkaline phosphatase during osteoblastic cell differentiation. Bone 30:91–98

    Article  PubMed  CAS  Google Scholar 

  44. Xiao G, Jiang D, Thomas P et al (2000) MAPK pathways activate and phosphorylate the osteoblast-specific transcription factor, Cbfa1. J Biol Chem 275:4453–4459

    Article  PubMed  CAS  Google Scholar 

  45. Cuadrado A, Nebreda AR (2010) Mechanisms and functions of p38 MAPK signalling. Biochem J 429:403–417

    Article  PubMed  CAS  Google Scholar 

  46. Rey A, Manen D, Rizzoli R, Ferrari SL, Caverzasio J (2007) Evidences for a role of p38 MAP kinase in the stimulation of alkaline phosphatase and matrix mineralization induced by parathyroid hormone in osteoblastic cells. Bone 41:59–67

    Article  PubMed  CAS  Google Scholar 

  47. Jessop HL, Rawlinson SC, Pitsillides AA, Lanyon LE (2002) Mechanical strain and fluid movement both activate extracellular regulated kinase (ERK) in osteoblast-like cells but via different signaling pathways. Bone 31:186–194

    Article  PubMed  CAS  Google Scholar 

  48. Kusumi A, Sakaki H, Kusumi T et al (2005) Regulation of synthesis of osteoprotegerin and soluble receptor activator of nuclear factor-kappaB ligand in normal human osteoblasts via the p38 mitogen-activated protein kinase pathway by the application of cyclic tensile strain. J Bone Miner Metab 23:373–381

    Article  PubMed  CAS  Google Scholar 

  49. Hatton JP, Pooran M, Li CF, Luzzio C, Hughes-Fulford M (2003) A short pulse of mechanical force induces gene expression and growth in MC3T3-E1 osteoblasts via an ERK 1/2 pathway. J Bone Miner Res 18:58–66

    Article  PubMed  CAS  Google Scholar 

  50. Wu Y, Zhang X, Zhang P, Fang B, Jiang L (2012) Intermittent traction stretch promotes the osteoblastic differentiation of bone mesenchymal stem cells by the ERK1/2-activated Cbfa1 pathway. Connect Tissue Res 53(6):451–459

    Article  PubMed  Google Scholar 

  51. Zhang P, Wu Y, Jiang Z, Jiang L, Fang B (2012) Osteogenic response of mesenchymal stem cells to continuous mechanical strain is dependent on ERK1/2-Runx2 signaling. Int J Mol Med 29:1083–1089

    PubMed  CAS  Google Scholar 

  52. Simmons CA, Matlis S, Thornton AJ, Chen S, Wang CY, Mooney DJ (2003) Cyclic strain enhances matrix mineralization by adult human mesenchymal stem cells via the extracellular signal-regulated kinase (ERK1/2) signaling pathway. J Biomech 36:1087–1096

    Article  PubMed  Google Scholar 

  53. Hotokezaka H, Sakai E, Kanaoka K et al (2002) U0126 and PD98059, specific inhibitors of MEK, accelerate differentiation of RAW264.7 cells into osteoclast-like cells. J Biol Chem 277:47366–47372

    Article  PubMed  CAS  Google Scholar 

  54. Zhang H, Shi X, Hampong M, Blanis L, Pelech S (2001) Stress-induced inhibition of ERK1 and ERK2 by direct interaction with p38 MAP kinase. J Biol Chem 276:6905–6908

    Article  PubMed  CAS  Google Scholar 

  55. Rubin J, Murphy TC, Zhu L, Roy E, Nanes MS, Fan X (2003) Mechanical strain differentially regulates endothelial nitric-oxide synthase and receptor activator of nuclear kappa B ligand expression via ERK1/2 MAPK. J Biol Chem 278:34018–34025

    Article  PubMed  CAS  Google Scholar 

  56. Tsuji K, Uno K, Zhang GX, Tamura M (2004) Periodontal ligament cells under intermittent tensile stress regulate mRNA expression of osteoprotegerin and tissue inhibitor of matrix metalloprotease-1 and -2. J Bone Miner Metab 22:94–103

    Article  PubMed  CAS  Google Scholar 

  57. Tazoe M, Mogi M, Goto S, Togari A (2003) Involvement of p38MAP kinase in bone morphogenetic protein-4-induced osteoprotegerin in mouse bone-marrow-derived stromal cells. Arch Oral Biol 48:615–619

    Article  PubMed  CAS  Google Scholar 

  58. Ulsamer A, Ortuno MJ, Ruiz S et al (2008) BMP-2 induces Osterix expression through up-regulation of Dlx5 and its phosphorylation by p38. J Biol Chem 283:3816–3826

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant No. 30901698, 10972142), the Collaborative Foundation of Medical and Engineering Science of Shanghai Jiaotong University (YG2012MS40), the Key Basic Research Foundation of the Shanghai Committee of Science and Technology, China (12JC1405700), and the Innovative Research Team of Shanghai Municipal Education Commission. We thank professor Jiang Zonglai and the Institute of Mechanobiology and Medical Engineering, Shanghai Jiao Tong University.

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Authors and Affiliations

  1. Center of Craniofacial Orthodontics, Department of Oral and Cranio-maxillofacial Science, Shanghai 9th People’s Hospital, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine, No. 639 Zhi-Zao-Ju Road, Shanghai, 200011, People’s Republic of China

    Peng Zhang, Yuqiong Wu, Qinggang Dai, Bing Fang & Lingyong Jiang

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  1. Peng Zhang
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  2. Yuqiong Wu
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  3. Qinggang Dai
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Correspondence to Bing Fang or Lingyong Jiang.

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Zhang, P., Wu, Y., Dai, Q. et al. p38-MAPK signaling pathway is not involved in osteogenic differentiation during early response of mesenchymal stem cells to continuous mechanical strain. Mol Cell Biochem 378, 19–28 (2013). https://doi.org/10.1007/s11010-013-1589-7

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  • DOI: https://doi.org/10.1007/s11010-013-1589-7

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