Which Activates Mechanotransduction in Bone—Extracellular Fluid Flow or Mechanical Strain?

  • Ichiro Owan
  • Kunio Ibaraki
  • Randall L. Duncan
  • Charles H. Turner
  • David B. Burr
Conference paper


We have defined mechanocoupling as the transduction of applied mechanical forces into a local mechanical signal which bone cells can perceive. Two candidates for this localized phenomenon are substrate strain or fluid flow within the bone matrix. Studies using the rat tibial 4-point bending model show that dynamic loads but not static loads increase bone formation, suggesting fluid flow as the machanical determinant of bone adaptation. To study the effects of these candidates on the osteoblast, MC3T3-E1 cells were grown on type I collagen-coated plastic plates and subjected to 4-point bending. Varying levels of substrate strain and fluid effects can be created independently in this system. Osteopontin (OPN) mRNA expression was used to assess the anabolic response of MC3T3-E1 cells. When fluid flow was low, neither strain magnitude nor strain rate was correlated with OPN expression. However, a higher magnitude of fluid flow significantly increased OPN mRNA expression independent of the strain magnitude or rate. We conclude that extracellular fluid flow might be more important than deformation of cell substrate in bone formation in response to mechanical loading.

Key words

Mechanical strain Fluid flow Mechanotransduction Osteoblasts Osteopontin 


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  1. 1.
    Simmons DJ, Russell JE, Winter F, Tran Van P, Vignery A, Baron R, Rosenberg GD, Walker WV (1983) Effect of spaceflight on the non-weight-bearing bones of rat skeleton. Am J Physiol 244:R319–R326PubMedGoogle Scholar
  2. 2.
    Patterson-Buckendahl PE, Grindeland RE, Martin RB, Cann CE, Arnaud SB (1985) Osteocalcin as an indicator of bone metabolism during spaceflight. Physiologist 28:S227–S228PubMedGoogle Scholar
  3. 3.
    Uhthoff HK, Jaworski ZFG (1978) Bone loss in response to long term immobilization. J Bone Joint Surg 60B:420–429Google Scholar
  4. 4.
    Morey ER, Baylink DJ (1978) Inhibition of bone formation during spaceflight. Science 201:1138–1141PubMedCrossRefGoogle Scholar
  5. 5.
    Wronski TJ, Morey ER (1983) Inhibition of cortical and trabecular bone formation in the long bones of immobilized monkeys. Clin Orthop Rel Res 181:269–276Google Scholar
  6. 6.
    Cann CE, Adachi RR (1983) Bone resorption and mineral excretion in rats during spaceflight. Am J Physiol 244:R327–R331PubMedGoogle Scholar
  7. 7.
    Weinreb M, Rodan GA, Thompson DD (1991) Immobilization-related bone loss in rat is increased by calcium deficiency. Calcif Tissue Int 48:93–100PubMedCrossRefGoogle Scholar
  8. 8.
    Vico L, Chappard D, Alexandre C, Palle S, Minaire P, Riffat G, Murukov B, Rakhmanov S (1987) Effects of a 120-day period of bed rest on bone mass and bone cell activities in man: attempts at countermeasure. Bone Miner 2:383–394PubMedGoogle Scholar
  9. 9.
    Rambaut PC, Johnston RS (1979) Prolonged weightlessness and calcium loss in man. Acta Astronaut 6:1113–1122PubMedCrossRefGoogle Scholar
  10. 10.
    Rubin CT, Lanyon LE (1984) Regulation of bone formation by applied dynamic loads. J Bone Joint Surg 66A.397–402Google Scholar
  11. 11.
    Sessions ND, Halloran BP, Binkle DD, Wronski TJ, Cone CM, Morey-Holton ER (1989) Bone response to normal weight bearing after a period of skeletal unloading. Am J Physiol 257:E606–E610PubMedGoogle Scholar
  12. 12.
    Somjen D, Binderman I, Burger EH, Harell A (1980) Bone remodeling induced by physical stress is prostaglandin E2 mediated. Biochim Biophys Acta 627:91–100PubMedCrossRefGoogle Scholar
  13. 13.
    Binderman I, Shimshoni Z, Somjen D (1984) Biochemical pathways involved in the translation of physical stimulus into biological message. Calcif Tissue Int 36 (Suppl):582–585CrossRefGoogle Scholar
  14. 14.
    Sandy JR, Meghji S, Farndale RW, Meikle MC (1989) Dual evaluation of cyclic AMP and inositol phosphates in response to mechanical deformation of murine osteoblasts. Biochim Biophys Acta 1010:265–269PubMedCrossRefGoogle Scholar
  15. 15.
    Burr DB, Milgrom C, Fyhrie D, Forwood M, Nyska M, Finestone A, Hoshaw S, Saiag E, Simkin S (1996) In vivo measurement of human tibial strains during vigorous activity. Bone 18:405–410PubMedCrossRefGoogle Scholar
  16. 16.
    Otter MW, Palmieri VR, Wu DD, Seiz KG, MacGinitie LA, Cochran GVB (1992) A comparative analysis of streaming potentials in vivo and in vitro. J Orthop Res 10:710–719PubMedCrossRefGoogle Scholar
  17. 17.
    Reich KM, Gay CV, Frangos JA (1990) Fluid shear stress as a mediator of osteoblast cyclic adenosine monophosphate production. J Cell Physiol 143:100–104PubMedCrossRefGoogle Scholar
  18. 18.
    Reich KM, Frangos JA (1993) Protein kinase C mediates flow-induced prostaglandin E2 production in osteoblasts. Calcif Tissue Int 52:62–66PubMedCrossRefGoogle Scholar
  19. 19.
    Johnson DL, McAllister TN, Frangos JA (1996) Fluid flow stimulates rapid and continuous release of nitric oxide in osteoblasts. Am J Physiol 271:E205–E208PubMedGoogle Scholar
  20. 20.
    Turner CH, Forwood MR, Yoshikawa T (1994) Mechanical loading thresholds for lamellar and woven bone formation. J Bone Min Res 9:87–97CrossRefGoogle Scholar
  21. 21.
    Turner CH, Owan I, Takano Y (1995) Mechanotransduction in bone: role of strain rate. Am J Physiol 269:E438–E442PubMedGoogle Scholar
  22. 22.
    Turner CH, Forwood MR, Otter MW (1994) Mechanotransduction in bone: do bone cells act as sensors of fluid flow? FASEB J 8:875–878PubMedGoogle Scholar
  23. 23.
    Owan I, Burr DB, Turner CH, Qui J, Tu Y, Onyia JE, Duncan RL (1997) Mechanotransduction in bone: osteoblasts are more responsive to fluid forces than mechanical strain. Am J Physiol 273:C810–C815PubMedGoogle Scholar
  24. 24.
    Klein-Nulend J, Van Der Plas A, Semeins CM, Ajubi NE, Frangos JA, Nijweide PJ, Burger EH (1995) Sensitivity of osteocytes to biomechanical stress in vitro. FASEB J 9:441–445PubMedGoogle Scholar
  25. 25.
    Resnick N, Collins T, Atkinson W, Bonthron RT, Dewey CF Jr, Gimbron MA Jr (1993) Platelet-derived growth factor B chain promoter contains a cis-acting fluid shear-stress-responsive element. Proc Natl Acad Sci USA 90:7908–7910PubMedCrossRefGoogle Scholar
  26. 26.
    Resnick N, Gimbrone MA Jr (1995) Hemodynamic forces are complex regulators of endothelial gene expression. FASEB J 9:874–882PubMedGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 1999

Authors and Affiliations

  • Ichiro Owan
    • 1
  • Kunio Ibaraki
    • 1
  • Randall L. Duncan
    • 2
  • Charles H. Turner
    • 2
  • David B. Burr
    • 2
  1. 1.Department of Orthopedic Surgery, Faculty of MedicineUniversity of the RyukyusNishihara, OkinawaJapan
  2. 2.Department of Orthopedic Surgery and The Biomechanics and Biomaterials Research CenterIndiana University Medical CenterIndianapolisUSA

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