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Regulation of synthesis of osteoprotegerin and soluble receptor activator of nuclear factor-κB ligand in normal human osteoblasts via the p38 mitogen-activated protein kinase pathway by the application of cyclic tensile strain

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Abstract

Mechanical stress is thought to play an important role in bone remodeling. However, the correlation between mechanical stress and bone remodeling is poorly understood. In this context, using a model of cyclic tensile strain (CTS) toward human osteoblasts, synthesis of osteoprotegerin (OPG) and soluble receptor activator of nuclear factor-κB ligand (sRANKL), and the activation of mitogen-activated protein kinases (MAPKs) were examined. The application of 7%, 0.25-Hz CTS once a day for 4 h for 3 successive days simultaneously caused an increase of OPG synthesis and a decrease of sRANKL release and RANKL mRNA expression in osteoblasts. As for MAPKs activation in osteoblasts with the application of CTS, p38 MAPK was activated 10–20 min after the application of CTS, but extracellular signal-regulated kinase (ERK1/2) and c-Jun NH2-terminal kinase (JNK) were not activated by such application. Furthermore, when CTS was applied once a day for 4 h for 1, 2, or 3 successive days to osteoblasts, p38 MAPK activation was maintained during the 3-day period but ERK1/2 activation was downregulated from day to day, simultaneously. Then, when CTS was applied once a day for 4 h for 3 successive days to osteoblasts pretreated with the p38 MAPK inhibitor SB203580 for 1 h, OPG synthesis was dose-dependently suppressed and inhibition of sRANKL release and RANKL mRNA expression was abrogated. These results indicate that biological responses of OPG and sRANKL synthesis in osteoblasts to the application of CTS are regulated via the p38 MAPK pathway and suggest that CTS might modulate and regulate bone metabolism.

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References

  1. TM Skerry (1999) ArticleTitleIdentification of novel signaling pathways during functional adaptation of the skeleton to mechanical loading: the role of glutamate as a paracrine signaling agent in the skeleton J Bone Miner Metab 17 66–70 Occurrence Handle10.1007/s007740050067 Occurrence Handle10084405

    Article  PubMed  Google Scholar 

  2. Y Mikuni-Takagaki (1999) ArticleTitleMechanical responses and signal transduction pathways in stretched osteocytes J Bone Miner Metab 17 57–60 Occurrence Handle10.1007/s007740050065 Occurrence Handle10084403

    Article  PubMed  Google Scholar 

  3. R Huiskes R Ruimerman GH van Lenthe JD Janssen (2000) ArticleTitleEffects of mechanical forces on maintenance and adaptation of form in trabecular bone Nature 405 704–706 Occurrence Handle10.1038/35015116 Occurrence Handle10864330

    Article  PubMed  Google Scholar 

  4. N Basso JNM Heersche (2002) ArticleTitleCharacteristics of in vitro osteoblastic cell loading models Bone 30 347–351 Occurrence Handle10.1016/S8756-3282(01)00678-0 Occurrence Handle11856641

    Article  PubMed  Google Scholar 

  5. Y Azuma M Ito Y Harada H Takagi T Ohta S Jingushi (2001) ArticleTitleLow-intensity pulsed ultrasound accelerates rat femoral fracture healing by acting on the various cellular reactions in the fracture callus J Bone Miner Res 16 671–680 Occurrence Handle11315994

    PubMed  Google Scholar 

  6. L Vico M Hinsenkamp D Jones PJ Marie A Zallone R Cancedda (2001) ArticleTitleOsteobiology, strain, and microgravity. Part II: studies at the tissue level Calcif Tissue Int 68 1–10 Occurrence Handle12037617

    PubMed  Google Scholar 

  7. N Takahashi N Udagawa T Suda (1999) ArticleTitleA new member of tumor necrosis factor ligand family, ODF/OPGL/TRANCE/RANKL, regulates osteoclast differentiation and function Biochem Biophys Res Commun 256 449–455 Occurrence Handle10.1006/bbrc.1999.0252 Occurrence Handle10080918

    Article  PubMed  Google Scholar 

  8. S Khosla (2001) ArticleTitleMinireview: the OPG/RANKL/RANK system Endocrinology 142 5050–5055 Occurrence Handle10.1210/en.142.12.5050 Occurrence Handle11713196

    Article  PubMed  Google Scholar 

  9. LC Hofbauer AE Heufelder (2001) ArticleTitleRole of receptor activator of nuclear factor-κB ligand and osteoprotegerin in bone cell biology J Mol Med 79 243–253 Occurrence Handle11485016

    PubMed  Google Scholar 

  10. QK Tran K Ohashi H Watanabe (2000) ArticleTitleCalcium signaling in endothelial cells Cardiovasc Res 48 113–122 Occurrence Handle10.1016/S0008-6363(00)00172-3

    Article  Google Scholar 

  11. MC Horowitz Y Xi K Wilson MA Kacena (2000) ArticleTitleControl of osteoclastogenesis and bone resorption by members of the TNF family of receptors and ligands Cytokine Growth Factor Rev 12 9–18 Occurrence Handle10.1016/S1359-6101(00)00030-7

    Article  Google Scholar 

  12. MA Bogoyevitch (2000) ArticleTitleSignaling via stress-activated mitogen-activated protein kinases in the cardiovascular system Cardiovasc Res 45 826–842 Occurrence Handle10.1016/S0008-6363(99)00386-7 Occurrence Handle10728408

    Article  PubMed  Google Scholar 

  13. S Matsuda H Kawasaki T Moriguchi Y Gotoh E Nishida (1995) ArticleTitleActivation of protein kinase cascades by osmotic shock J Biol Chem 270 12781–12786 Occurrence Handle10.1074/jbc.270.19.11037 Occurrence Handle7759532

    Article  PubMed  Google Scholar 

  14. Y Seko K Tobe K Ueki T Kadowaki Y Yazaki (1996) ArticleTitleHypoxia and hypoxia/reoxygenation activate Raf-1, mitogen-activated protein kinase kinase, mitogen-activated protein kinases, and S6 kinase in cultured rat cardiac myocytes Circ Res 78 82–90 Occurrence Handle8603510

    PubMed  Google Scholar 

  15. S Le TJ Connors AC Maroney (2001) ArticleTitlec-Jun N-terminal kinase specifically phosphorylates p66ShcA at serine 36 in response to ultraviolet irradiation J Biol Chem 276 48332–48336 Occurrence Handle11602589

    PubMed  Google Scholar 

  16. I Sanchez RT Hughes BJ Mayer K Yee JR Woodgett J Avruch JM Kyriakis LI Zon (1994) ArticleTitleRole of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun Nature 372 794–798 Occurrence Handle7997269

    PubMed  Google Scholar 

  17. C Widmann S Gibson MB Jarpe GL Johnson (1999) ArticleTitleMitogen-activated protein kinase: conservation of a three-kinase module from yeast to human Physiol Rev 79 143–180 Occurrence Handle9922370

    PubMed  Google Scholar 

  18. HL Jessop SC Rawlinson AA Pitsillides LE Lanyon (2002) ArticleTitleMechanical strain and fluid movement both activate extracellular regulated kinase (ERK) in osteoblast-like cells but via different signaling pathways Bone 31 186–194 Occurrence Handle10.1016/S8756-3282(02)00797-4 Occurrence Handle12110433

    Article  PubMed  Google Scholar 

  19. JP Hatton M Pooran C-F Li C Luzzio M Hughes-Fulford (2003) ArticleTitleA 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 Occurrence Handle12510806

    PubMed  Google Scholar 

  20. K Tsuji K Uno GX Zhang M Tamura (2004) ArticleTitlePeriodontal 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 Occurrence Handle10.1007/s00774-003-0456-0 Occurrence Handle14999519

    Article  PubMed  Google Scholar 

  21. M Tazoe M Mogi S Goto A Togari (2003) ArticleTitleInvolvement of p38MAP kinase in bone morphogenetic protein-4-induced osteoprotegerin in mouse bone-marrow-derived stromal cells Arch Oral Biol 48 615–619 Occurrence Handle10.1016/S0003-9969(03)00100-6 Occurrence Handle12828991

    Article  PubMed  Google Scholar 

  22. A Kusumi T Abo T Masuda K Sugiura T Seki T Ohteki R Okuyama K Kumagai (1992) ArticleTitleLymphotoxin activates hepatic T cells and simultaneously induces profound thymic atrophy Immunol 77 177–184

    Google Scholar 

  23. A Kusumi H H. Sakaki R Fukui H Satoh T Kusumi H Kimura (2004) ArticleTitleHigh IL-6 synthesis in cultured fibroblasts isolated from radicular cysts Arch Oral Biol 49 643–652 Occurrence Handle10.1016/j.archoralbio.2004.02.006 Occurrence Handle15196982

    Article  PubMed  Google Scholar 

  24. K Naruse T Yamada M Sokabe (1998) ArticleTitleInvolvement of SA channels in orienting response of cultured endothelial cells to cyclic stretch Am J Physiol 274 H1532–H1538 Occurrence Handle9612360

    PubMed  Google Scholar 

  25. H Kimura A Narita M Akanuma R Fukui W Kobayashi A Kusumi (1999) ArticleTitlePathogenesis of jaw cyst enlargement Hirosaki Med J 51 IssueIDSuppl S54–S60

    Google Scholar 

  26. I Bièche I Laurendeau S Tozlu M Olivi D Vidaud R Lidereau M Vidaud (1999) ArticleTitleQuantitation of MYC gene expression in sporadic breast tumors with a real-time reverse transcription-PCR assay Cancer Res 1999 IssueID59 2759–2765

    Google Scholar 

  27. T Hiroi M Yanagita N Ohta G Sakaue H Kiyono (2000) ArticleTitleIL-15 and IL-15 receptor selectively regulate differentiation of common mucosal immune system-independent B-1 cells for IgA responses J Immunol 165 4329–4337 Occurrence Handle11035068

    PubMed  Google Scholar 

  28. S Chretien A Dubart D Beaupain N Raich B Grandchamp J Rosa M Goossens P-H Romeo (1988) ArticleTitleAlternative transcription and splicing of the human porphobilinogen deaminase gene result either in tissue-specific or in housekeeping expression Proc Natl Acad Sci U S A 1988 IssueID85 6–10

    Google Scholar 

  29. S Weinbaum SC Cowin Y Zeng (1994) ArticleTitleA model for the excitation of osteocytes by mechanical loading-induced bone fluid shear stresses J Biomech 27 339–360 Occurrence Handle10.1016/0021-9290(94)90010-8 Occurrence Handle8051194

    Article  PubMed  Google Scholar 

  30. M Matsumoto T Sudo T Saito H Osada M Tsujimoto (2000) ArticleTitleInvolvement of p38 mitogen-activated protein kinase signaling pathway in osteoclastogenesis mediated by receptor activator of NF-κB ligand (RANKL) J Biol Chem 275 31155–31161 Occurrence Handle10.1074/jbc.M001229200 Occurrence Handle10859303

    Article  PubMed  Google Scholar 

  31. C Granet N Boutahar L Vico C Alexandre MH Lafage-Proust (2001) ArticleTitleMAPK and SRC-kinases control EGR-1 and NF-κB inductions by changes in mechanical environment in osteoblasts Biochem Biophys Res Commun 284 622–631 Occurrence Handle10.1006/bbrc.2001.5023 Occurrence Handle11396946

    Article  PubMed  Google Scholar 

  32. S Theoleyre Y Wittrant S Couillaud P Vusio M Berreur C Dunstan F Blanchard F Redini D Heymann (2004) ArticleTitleCellular activity and signaling induced by osteoprotegerin in osteoclasts: involvement of receptor activator of nuclear factor κB ligand and MAPK Biochim Biophys Acta 1644 1–7 Occurrence Handle10.1016/j.bbamcr.2003.10.005 Occurrence Handle14741739

    Article  PubMed  Google Scholar 

  33. Y Kobayashi F Hashimoto H Miyamoto K Kanaoka Y Miyazaki-Kawashita T Nakashima M Shibata K Kobayashi Y Kato H Sakai (2000) ArticleTitleForce-induced osteoclast apoptosis in vivo is accompanied by elevation in transforming growth factor β and osteoprotegerin expression J Bone Miner Res 15 1924–1934 Occurrence Handle11028444

    PubMed  Google Scholar 

  34. J Rubin TC Murphy L Zhu E Roy MS Nanes X Fan (2003) ArticleTitleMechanical strain differentially regulates endothelial nitric-oxide synthase and receptor activator of nuclear κB ligand expression via ERK1/2 MAPK J Biol Chem 278 34018–34025 Occurrence Handle10.1074/jbc.M302822200 Occurrence Handle12824189

    Article  PubMed  Google Scholar 

  35. FA Peverali EK Basdra AG Papavassiliou (2001) ArticleTitleStretch-mediated activation of selective MAPK subtypes and potentiation of AP-1 binding in human osteoblastic cells Mol Med 7 68–78 Occurrence Handle11474129

    PubMed  Google Scholar 

  36. HL Jessop M Sjöberg MZ Cheng G Zaman CPD Wheeler-Jones LE Lanyon (2001) ArticleTitleMechanical strain as well as estrogen activates estrogen receptor α in bone cells J Bone Miner Res 16 1045–1055 Occurrence Handle11393781

    PubMed  Google Scholar 

  37. R Sugiura A Kita Y Shimizu H Shuntoh SO Sio T Kuno (2004) ArticleTitleFeedback regulation of MAPK signalling by an RNA-binding protein Nature 424 961–965 Occurrence Handle10.1038/nature01907

    Article  Google Scholar 

  38. M Alvarado-Kristensson T Andersson (2005) ArticleTitleProtein phosphatase 2A regulates apoptosis in neutrophils by dephosphorylating both p38 MAPK and its substrate caspase 3 J Biol Chem 280 6238–6244 Occurrence Handle10.1074/jbc.M409718200 Occurrence Handle15569672

    Article  PubMed  Google Scholar 

  39. E Terpos R Szydlo JF Apperley E Hatjiharissi M Politou J Meletis N Viniou X Yataganas JM Goldman A Rahemtulla (2003) ArticleTitleSoluble receptor activator of nuclear factor κB ligand-osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index Blood 102 1064–1069 Occurrence Handle10.1182/blood-2003-02-0380 Occurrence Handle12689925

    Article  PubMed  Google Scholar 

  40. B Pan AN Farrugia LB To DM Findlay J Green K Lynch AC Zannettino (2004) ArticleTitleThe nitrogen-containing bisphosphonate, zoledronic acid, influences RANKL expression in human osteoblast-like cells by activating TNF-α converting enzyme (TACE) J Bone Miner Res 19 147–154 Occurrence Handle14753746

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Dentistry and Oral Surgery, National University Corporation, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan

    Akinori Kusumi, Hirotaka Sakaki, Mitsuo Oda, Kenji Narita, Hiroshi Nakagawa, Kohsei Kubota, Hisashi Satoh & Hiroto Kimura

  2. Second Department of Pathology, National University Corporation, Hirosaki University School of Medicine, Hirosaki, Japan

    Tomomi Kusumi

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  1. Akinori Kusumi
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  2. Hirotaka Sakaki
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Correspondence to Akinori Kusumi.

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Kusumi, A., Sakaki, H., Kusumi, T. et al. Regulation of synthesis of osteoprotegerin and soluble receptor activator of nuclear factor-κB 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 (2005). https://doi.org/10.1007/s00774-005-0615-6

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  • DOI: https://doi.org/10.1007/s00774-005-0615-6

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