Skip to main content
SpringerLink
Log in

Cyclic fluid shear stress promotes osteoblastic cells proliferation through ERK5 signaling pathway

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Fluid shear stress plays an important role in bone remodeling, however, the mechanism of mechanotransduction in bone tissue remains unclear. Recently, ERK5 has been found to be involved in multiple cellular processes. This study was designed to investigate the potential involvement of ERK5 in the proliferative response of osteoblastic cells to cyclic fluid shear stress. We reported here that cyclic fluid shear stress promoted ERK5 phosphorylation in MC3T3-E1 cells. Inhibition of ERK5 phosphorylation attenuated the increased expression of AP-1 and cyclin D1 and cell proliferation induced by cyclic fluid flow, but promoted p-16 expression. Further more, we found that cyclic fluid shear stress was a better stimuli for ERK5 activation and cyclin D1 expression compared with continuous fluid shear stress. Moreover, the pharmacological ERK5 inhibitor, BIX02189, which inhibited ERK5 phosphorylation in a time-dependent manner and the suppression lasted for at least 4 h. Taken together, we demonstrate that ERK5/AP-1/cyclin D1 pathway is involved in the mechanism of osteoblasts proliferation induced by cyclic fluid shear stress, which is superior in promoting cellular proliferation compared with continuous fluid shear stress.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Kawamura N, Kugimiya F, Oshima Y, Ohba S, Ikeda T, Saito T, Shinoda Y, Kawasaki Y, Ogata N, Hoshi K, Akiyama T, Chen WS, Hay N, Tobe K, Kadowaki T, Azuma Y, Tanaka S, Nakamura K, Chung UI, Kawaguchi H (2007) Akt1 in osteoblasts and osteoclasts controls bone remodeling. PLoS ONE 2:e1058

    Article  PubMed  Google Scholar 

  2. Reich KM, Gay CV, Frangos JA (1990) Fluid shear stress as a mediator of osteoblast cyclic adenosine monophosphate production. J Cell Physiol 143:100–104

    Article  PubMed  CAS  Google Scholar 

  3. Takai E, Mauck RL, Hung CT, Guo XE (2004) Osteocyte viability and regulation of osteoblast function in a 3D trabecular bone explant under dynamic hydrostatic pressure. J Bone Miner Res 19:1403–1410

    Article  PubMed  Google Scholar 

  4. Basso N, Heersche JNM (2002) Characteristics of in vitro osteoblastic cell loading models. Bone 30:347–351

    Article  PubMed  CAS  Google Scholar 

  5. Biewener AA, Taylor CR (1986) Bone strain: a determinant of gait and speed? J Exp Biol 123:383–400

    PubMed  CAS  Google Scholar 

  6. Myers KA, Rattner JB (2007) Osteoblast-like cells and fluid flow: cytoskeleton-dependent shear sensitivity. Biochem Biophys Res Commun 364:214–219

    Article  PubMed  CAS  Google Scholar 

  7. Majima T, Marchuk LL, Sciore P, Shrive NG, Frank CB, Hart DA (2000) Compressive compared with tensile loading of medial collateral ligament scar in vitro uniquely influences mRNA levels for aggrecan, collagen type II, and collagenase. J Orthop Res 18:524–531

    Article  PubMed  CAS  Google Scholar 

  8. Kim IS, Song YM, Cho TH, Kim JY, Weber FE, Hwang SJ (2009) Synergistic action of static stretching and BMP-2 stimulation in the osteoblast differentiation of C2C12 myoblasts. J Biomech 42(16):2721–2727

    Article  PubMed  Google Scholar 

  9. Sakai K, Mohtai M, Iwamoto Y (1998) Fluid shear stress increases transforming growth factor beta 1 expression in human osteoblast-like cells: modulation by cation channel blockades. Calcif Tissue Int 63:515–520

    Article  PubMed  CAS  Google Scholar 

  10. Liu D, Genetos DC, Shao Y, Geist DJ, Li J, Ke HZ, Turner CH, Duncan RL (2008) Activation of extracellular-signal regulated kinase (ERK1/2) by fluid shear is Ca2+- and ATP-dependent in MC3T3-E1 osteoblasts. Bone 42:644–652

    Article  PubMed  CAS  Google Scholar 

  11. Fukuno N, Matsui H, Kanda Y, Suzuki O, Matsumoto K, Sasaki K, Kobayashi T, Tamura S (2011) TGF-[beta]-activated kinase 1 mediates mechanical stress-induced IL-6 expression in osteoblasts. Biochem Biophys Res Commun 408:202–207

    Article  PubMed  CAS  Google Scholar 

  12. Lee J-D, Levtch RJU, Han J (1995) Primary structure of BMK1: a new mammalian MAP kinase. Biochem Biophys Res Commun 213:715–724

    Article  PubMed  CAS  Google Scholar 

  13. Pi X, Yan C, Berk BC (2003) Big mitogen-activated protein kinase (BMK1)/ERK5 protects endothelial cells from apoptosis. Circ Res 94:362–369

    Article  PubMed  Google Scholar 

  14. Dinev D, Jordan BWM, Neufeld B, Lee J-D, Lindemann D, RappS UR, Ludwig S (2001) Extracellular signal regulated kinase 5 (ERK5) is required for the differentiation of muscle cells. EMBO Rep 2:829–834

    Article  PubMed  CAS  Google Scholar 

  15. Mehta P, Jenkins B, McCarthy L, Thilak L, Robson C, Neal D, Leung H (2003) MEK5 overexpression is associated with metastatic prostate cancer, and stimulates proliferation, MMP-9 expression and invasion. Oncogene 22:1381–1389

    Article  PubMed  CAS  Google Scholar 

  16. Yan L, Carr J, Ashby PR, Murry-Tait V, Thompson C, Arthur JSC (2003) Knockout of ERK5 causes multiple defects in placental and embryonic development. BMC Dev Biol 3:11–31

    Article  PubMed  Google Scholar 

  17. Yan C, Takahashi M, Okuda M, Lee J-D, Berk C (1999) Fluid shear stress stimulates big mitogen-activated protein kinase 1 (BMK1) activity in endothelial cells. Dependence on tyrosine kinases and intracellular calcium. J Biol Chem 274:143–150

    Article  PubMed  CAS  Google Scholar 

  18. Huang Y-C, Hung W-C, Chen W-T, Jiang W-H, Yu H-S, Chai C-Y (2011) Effects of MEK and DNMT inhibitors on arsenic-treated human uroepithelial cells in relation to cyclin-D1 and p16. Toxicol Lett 200:59–66

    Article  PubMed  CAS  Google Scholar 

  19. Mulloy R, Salinas S, Philips A, Hipskind RA (2003) Activation of cyclin D1 expression by the ERK5 cascade. Oncogene 22:5387–5398

    Article  PubMed  CAS  Google Scholar 

  20. Tatake RJ, O’Neill MM, Kennedy CA, Wayne AL, Jakes S, Wu D, Kugler SZ Jr, Kashem MA, Kaplita P, Snow RJ (2008) Identification of pharmacological inhibitors of the MEK5/ERK5 pathway. Biochem Biophys Res Commun 377(1):120–125

    Article  PubMed  CAS  Google Scholar 

  21. Abe J-I, Kusuhara M, Ulevitch RJ, Berk BC, Lee J-D (1996) Big mitogen-activated protein kinase 1 (BMK1) is a redox-sensitive kinase. J Biol Chem 271:16586–16590

    Article  PubMed  CAS  Google Scholar 

  22. Frangos JA, McIntire LV, Eskin SG (1987) Shear stress induced stimulation of mammalian cell metabolism. Biotechnol Bioeng 32:1053–1060

    Article  Google Scholar 

  23. Hsieh T-P, Sheu S-Y, Sun J-S, Chen M-H (2011) Icariin inhibits osteoclast differentiation and bone resorption by suppression of MAPKs/NF-kB regulated HIF-1a and PGE2 synthesis. Phytomedicine 18:176–185

    Article  PubMed  CAS  Google Scholar 

  24. Keselowsky BG, Collard DM, García AJ (2005) Integrin binding specificity regulates biomaterial surface chemistry effects on cell differentiation. Proc Natl Acad Sci 102:5953–5957

    Article  PubMed  CAS  Google Scholar 

  25. Yang Q, Lee J-D (2011) Targeting the BMK1 MAP kinase pathway in cancer therapy. Neurosci Lett 494:38–43

    Article  Google Scholar 

  26. Li L, Tatake RJ, Natarajan K, Taba Y, Garin G, Tai C, Leung E, Surapisitchat J, Yoshizumi M, Yan C, Abe J-I, Berk BC (2008) Fluid shear stress inhibits TNF-mediated JNK activation via MEK5-BMK1 in endothelial cells. Biochem Biophys Res Commun 370:159–163

    Article  PubMed  CAS  Google Scholar 

  27. Jia X, Liu B, Shi X, Ye M, Zhang F, Liu H (2011) Roles of the ERK, JNK/AP-1/cyclin D1-CDK4 pathway in silica-induced cell cycle changes in human embryo lung fibroblast cells. Cell Biol Int 35:697–704

    Article  PubMed  CAS  Google Scholar 

  28. Coqueret O (2002) Linking cyclins to transcriptional control. Gene 299:35–55

    Article  PubMed  CAS  Google Scholar 

  29. Nauman EA, Satcher RL, Keaveny TM, Halloran BP, Bikle DD (2001) Osteoblasts respond to pulsatile fluid flow with shortterm increases in PGE2 but no change in mineralization. J Appl Physiol 90:1849–1854

    PubMed  CAS  Google Scholar 

  30. Jacobsa CR, Yellowley CE, Davis BR, Zhou Z, Cimbala JM, Donahuea HJ (1998) Differential effect of steady versus oscillating flow on bone cells. J Biomech 11:969–976

    Article  Google Scholar 

  31. Hwang J, Ing MH, Salazar A, Lassègue B, Griendling K, Navab M, Sevanian A, Hsiai TK (2003) Pulsatile versus oscillatory shear stress regulates NADPH oxidase subunit expression implication for native LDL oxidation. Circ Res 93:1225–1232

    Article  PubMed  CAS  Google Scholar 

  32. Young SRL, Hum JM, Rodenberg E, Turner CH, Pavalko FM (2011) Non-overlapping functions for Pyk2 and FAK in osteoblasts during fluid shear stress-induced mechanotransduction. Plos One 6:e16026

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Natural Science Foundation of China (Grant No. 81071478). The authors are very grateful to Boehringer Ingelheim for their kindly providing of ERK5 inhibitors, BIX02188, and BIX02189.

Author information

Authors and Affiliations

  1. Institute of Orthopaedics, The Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, People’s Republic of China

    Peng Li, Xiao-yun Sheng, Hai-tao Dong, Jing Wang & Ya-yi Xia

  2. Department of Orthopaedics, The Lanzhou University Second Hospital, Lanzhou, 730000, Gansu, People’s Republic of China

    Yan-chao Ma, Hua Han & Ya-yi Xia

Authors
  1. Peng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yan-chao Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiao-yun Sheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hai-tao Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hua Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ya-yi Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ya-yi Xia.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, P., Ma, Yc., Sheng, Xy. et al. Cyclic fluid shear stress promotes osteoblastic cells proliferation through ERK5 signaling pathway. Mol Cell Biochem 364, 321–327 (2012). https://doi.org/10.1007/s11010-012-1233-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-012-1233-y

Keywords

Search

Navigation