Using Cell and Organ Culture Models to Analyze Responses of Bone Cells to Mechanical Stimulation

  • Soraia P. Caetano-Silva
  • Astrid Novicky
  • Behzad Javaheri
  • Simon C. F. Rawlinson
  • Andrew A. PitsillidesEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1914)


The techniques that are useful for applying mechanical strain to bone and bone cells are now more diverse than described in the second Edition. Their output has also increased substantially and, perhaps most importantly, their significance is now broadly accepted. This growth in the use of methods for applying mechanical strain to bone and its constituent cells and increased awareness of the importance of the mechanical environment in controlling normal bone cell behavior has indeed heralded new therapeutic approaches. We have expanded the text to include additions and modifications made to the straining apparatus and updated the research cited to support this growing role of cell cultures, including co-culture systems and primary cells, tissue engineering, and organ culture models to analyze responses of bone cells to mechanical stimulation. We understand that there are approaches not covered here and appreciate that alternative strategies have their own value and utility.

Key words

Mechanical loading Strain Organ culture 



We are grateful to Arthritis Research UK, the Biotechnology and Biological Sciences Research Council, and The Wellcome Trust for their contribution to the work done in the laboratories of AAP. We would also like to thank Dr. Gul Zaman for his constructive and critical comments and Victoria Das-Gupta and Dominic Simon for their contributions to the original edition.

We are grateful that this work has received funding from the European Union’s Horizon 2020 research and innovation programme under Marie Sklodowska-Curie grant agreement No 721432.


  1. 1.
    Bradbeer JN (1992) In: Edwards CRE, Lincoln DW (eds) Cell biology of bone remodelling, in recent advances in endrocrinology and metabolism. Chruchill Livingstone, London, pp 95–113Google Scholar
  2. 2.
    Bacabac RG et al (2004) Nitric oxide production by bone cells is fluid shear stress rate dependent. Biochem Biophys Res Commun 315(4):823–829PubMedCrossRefGoogle Scholar
  3. 3.
    McBride SH, Silva MJ (2012) Adaptive and injury response of bone to mechanical loading. Bonekey Osteovision 1:192PubMedPubMedCentralGoogle Scholar
  4. 4.
    Chen JH et al (2010) Boning up on Wolff's law: mechanical regulation of the cells that make and maintain bone. J Biomech 43(1):108–118PubMedCrossRefGoogle Scholar
  5. 5.
    Ren L et al (2015) Biomechanical and biophysical environment of bone from the macroscopic to the pericellular and molecular level. J Mech Behav Biomed Mater 50:104–122PubMedCrossRefGoogle Scholar
  6. 6.
    Suswillo RF et al (2017) Strain uses gap junctions to reverse stimulation of osteoblast proliferation by osteocytes. Cell Biochem Funct 35(1):56–65PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Vazquez M et al (2014) A new method to investigate how mechanical loading of osteocytes controls osteoblasts. Front Endocrinol (Lausanne) 5:208CrossRefGoogle Scholar
  8. 8.
    Bonassar LJ et al (2000) Mechanical and physicochemical regulation of the action of insulin-like growth factor-I on articular cartilage. Arch Biochem Biophys 379(1):57–63PubMedCrossRefGoogle Scholar
  9. 9.
    Bayliss MT et al (2000) The organization of aggrecan in human articular cartilage. Evidence for age-related changes in the rate of aggregation of newly synthesized molecules. J Biol Chem 275(9):6321–6327PubMedCrossRefGoogle Scholar
  10. 10.
    Wong JK et al (2009) The cellular biology of flexor tendon adhesion formation: an old problem in a new paradigm. Am J Pathol 175(5):1938–1951PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Lynch ME, Fischbach C (2014) Biomechanical forces in the skeleton and their relevance to bone metastasis: biology and engineering considerations. Adv Drug Deliv Rev 79-80:119–134PubMedCrossRefGoogle Scholar
  12. 12.
    Nyman JS et al (2009) Differences in the mechanical behavior of cortical bone between compression and tension when subjected to progressive loading. J Mech Behav Biomed Mater 2(6):613–619PubMedCrossRefGoogle Scholar
  13. 13.
    Hellmich C, Ulm FJ (2002) Are mineralized tissues open crystal foams reinforced by crosslinked collagen?—some energy arguments. J Biomech 35(9):1199–1212PubMedCrossRefGoogle Scholar
  14. 14.
    Mercer C et al (2006) Mechanisms governing the inelastic deformation of cortical bone and application to trabecular bone. Acta Biomater 2(1):59–68PubMedCrossRefGoogle Scholar
  15. 15.
    Rubin CT, Lanyon LE (1984) Regulation of bone formation by applied dynamic loads. J Bone Joint Surg Am 66(3):397–402PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Bonnans C, Chou J, Werb Z (2014) Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol 15(12):786–801PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Hillam RA, Goodship AE, Skerry TM (2015) Peak strain magnitudes and rates in the tibia exceed greatly those in the skull: an in vivo study in a human subject. J Biomech 48(12):3292–3298PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Cheng MZ, Zaman G, Lanyon LE (1994) Estrogen enhances the stimulation of bone collagen synthesis by loading and exogenous prostacyclin, but not prostaglandin E2, in organ cultures of rat ulnae. J Bone Miner Res 9(6):805–816PubMedCrossRefGoogle Scholar
  19. 19.
    Hu K et al (2017) TRPV4 functions in flow shear stress induced early osteogenic differentiation of human bone marrow mesenchymal stem cells. Biomed Pharmacother 91:841–848PubMedCrossRefGoogle Scholar
  20. 20.
    Fritton SP, Weinbaum S (2009) Fluid and solute transport in bone: flow-induced mechanotransduction. Annu Rev Fluid Mech 41:347–374PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Anderson HJ et al (2016) Mesenchymal stem cell fate: applying biomaterials for control of stem cell behavior. Front Bioeng Biotechnol 4:38PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Wrighton PJ et al (2014) Signals from the surface modulate differentiation of human pluripotent stem cells through glycosaminoglycans and integrins. Proc Natl Acad Sci U S A 111(51):18126–18131PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Bellis SL (2011) Advantages of RGD peptides for directing cell association with biomaterials. Biomaterials 32(18):4205–4210PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Zimmerman D et al (2000) Impaired bone formation in transgenic mice resulting from altered integrin function in osteoblasts. Dev Biol 220(1):2–15PubMedCrossRefGoogle Scholar
  25. 25.
    Danmark S et al (2012) Integrin-mediated adhesion of human mesenchymal stem cells to extracellular matrix proteins adsorbed to polymer surfaces. Biomed Mater 7(3):035011PubMedCrossRefGoogle Scholar
  26. 26.
    Cowles EA, Brailey LL, Gronowicz GA (2000) Integrin-mediated signaling regulates AP-1 transcription factors and proliferation in osteoblasts. J Biomed Mater Res 52(4):725–737PubMedCrossRefGoogle Scholar
  27. 27.
    Flores ME et al (1996) Bone sialoprotein coated on glass and plastic surfaces is recognized by different beta 3 integrins. Exp Cell Res 227(1):40–46PubMedCrossRefGoogle Scholar
  28. 28.
    Schedel J et al (2004) Differential adherence of osteoarthritis and rheumatoid arthritis synovial fibroblasts to cartilage and bone matrix proteins and its implication for osteoarthritis pathogenesis. Scand J Immunol 60(5):514–523PubMedCrossRefGoogle Scholar
  29. 29.
    Lam MT, Longaker MT (2012) Comparison of several attachment methods for human iPS, embryonic and adipose-derived stem cells for tissue engineering. J Tissue Eng Regen Med 6(Suppl 3):s80–s86PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Collin-Osdoby P, Nickols GA, Osdoby P (1995) Bone cell function, regulation, and communication: a role for nitric oxide. J Cell Biochem 57(3):399–408PubMedCrossRefGoogle Scholar
  31. 31.
    Schiller PC et al (2001) Gap-junctional communication is required for the maturation process of osteoblastic cells in culture. Bone 28(4):362–369PubMedCrossRefGoogle Scholar
  32. 32.
    Chan M et al (2009) A trabecular bone explant model of osteocyte-osteoblast co-culture for bone mechanobiology. Cell Mol Bioeng 2(3):405–415PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Jeon OH et al (2016) Human iPSC-derived osteoblasts and osteoclasts together promote bone regeneration in 3D biomaterials. Sci Rep 6:26761PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Rinn JL et al (2006) Anatomic demarcation by positional variation in fibroblast gene expression programs. PLoS Genet 2(7):e119PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Everts V, de Vries TJ, Helfrich MH (2009) Osteoclast heterogeneity: lessons from osteopetrosis and inflammatory conditions. Biochim Biophys Acta 1792(8):757–765PubMedCrossRefGoogle Scholar
  36. 36.
    Rawlinson SCF et al (2009) Genetic selection for fast growth generates bone architecture characterised by enhanced periosteal expansion and limited consolidation of the cortices but a diminution in the early responses to mechanical loading. Bone 45:357–366PubMedCrossRefGoogle Scholar
  37. 37.
    Rawlinson SCF et al (2009) Adult rat bones maintain distinct regionalized expression of markers associated with their development. PLoS One 4(12):e8358PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Zhang W et al (2013) Tuning the poisson's ratio of biomaterials for investigating cellular response. Adv Funct Mater 23(25):3226–3232CrossRefGoogle Scholar
  39. 39.
    Caliari SR, Burdick JA (2016) A practical guide to hydrogels for cell culture. Nat Methods 13(5):405–414PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Engler AJ et al (2006) Matrix elasticity directs stem cell lineage specification. Cell 126(4):677–689PubMedCrossRefGoogle Scholar
  41. 41.
    Park JS et al (2011) The effect of matrix stiffness on the differentiation of mesenchymal stem cells in response to TGF-beta. Biomaterials 32(16):3921–3930PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Sztefek P et al (2010) Using digital image correlation to determine bone surface strains during loading and after adaptation of the mouse tibia. J Biomech 43(4):599–605PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Smith TS, Bay BK, Rashid MM (2002) Digital volume correlation including rotational degrees of freedom during minimization. Exp Mech 42(3):272–278CrossRefGoogle Scholar
  44. 44.
    Elsaadany M, Harris M, Yildirim-Ayan E (2017) Design and validation of equiaxial mechanical strain platform, EQUicycler, for 3D tissue engineered constructs. Biomed Res Int 2017:3609703PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Garcia-Cardena G et al (1998) Dynamic activation of endothelial nitric oxide synthase by Hsp90. Nature 392(6678):821–824PubMedCrossRefGoogle Scholar
  46. 46.
    Das P, Schurman DJ, Smith RL (1997) Nitric oxide and G proteins mediate the response of bovine articular chondrocytes to fluid-induced shear. J Orthop Res 15(1):87–93PubMedCrossRefGoogle Scholar
  47. 47.
    Villanueva I et al (2008) Static and dynamic compressive strains influence nitric oxide production and chondrocyte bioactivity when encapsulated in PEG hydrogels of different crosslinking densities. Osteoarthr Cartil 16(8):909–918PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Jessop HL et al (2002) Mechanical strain and fluid movement both activate extracellular regulated kinase (ERK) in osteoblast-like cells but via different signaling pathways. Bone 31(1):186–194PubMedCrossRefGoogle Scholar
  49. 49.
    Binderman I, Shimshoni Z, Somjen D (1984) Biochemical pathways involved in the translation of physical stimulus into biological message. Calcif Tissue Int 36(Suppl 1):S82–S85PubMedCrossRefGoogle Scholar
  50. 50.
    Hasegawa S et al (1985) Mechanical stretching increases the number of cultured bone cells synthesizing DNA and alters their pattern of protein synthesis. Calcif Tissue Int 37(4):431–436PubMedCrossRefGoogle Scholar
  51. 51.
    Ahmed WW, Kural MH, Saif TA (2010) A novel platform for in situ investigation of cells and tissues under mechanical strain. Acta Biomater 6(8):2979–2990PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Basdra EK, Kohl A, Komposch G (1996) Mechanical stretching of periodontal ligament fibroblasts–a study on cytoskeletal involvement. J Orofac Orthop 57(1):24–30PubMedCrossRefGoogle Scholar
  53. 53.
    Oortgiesen DA et al (2012) A three-dimensional cell culture model to study the mechano-biological behavior in periodontal ligament regeneration. Tissue Eng Part C Methods 18(2):81–89PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Soma S, Matsumoto S, Takano-Yamamoto T (1997) Enhancement by conditioned medium of stretched calvarial bone cells of the osteoclast-like cell formation induced by parathyroid hormone in mouse bone marrow cultures. Arch Oral Biol 42(3):205–211PubMedCrossRefGoogle Scholar
  55. 55.
    Andersen KL, Norton LA (1991) A device for the application of known simulated orthodontic forces to human cells in vitro. J Biomech 24(7):649–654PubMedCrossRefGoogle Scholar
  56. 56.
    Matsuo T, Uchida H, Matsuo N (1996) Bovine and porcine trabecular cells produce prostaglandin F2 alpha in response to cyclic mechanical stretching. Jpn J Ophthalmol 40(3):289–296PubMedGoogle Scholar
  57. 57.
    Bilgen B et al (2013) Design of a biaxial mechanical loading bioreactor for tissue engineering. J Vis Exp 74:e50387Google Scholar
  58. 58.
    Baker AB, Lee J (2015) Computational analysis of fluid flow within a device for applying biaxial strain to cultured cells. J Biomech Eng 137(5):051006PubMedCrossRefGoogle Scholar
  59. 59.
    DiFederico E, Shelton JC, Bader DL (2017) Complex mechanical conditioning of cell-seeded agarose constructs can influence chondrocyte biosynthetic activity. Biotechnol Bioeng 114(7):1614–1625PubMedCrossRefGoogle Scholar
  60. 60.
    Banes AJ et al (1985) A new vacuum-operated stress-providing instrument that applies static or variable duration cyclic tension or compression to cells in vitro. J Cell Sci 75:35–42PubMedGoogle Scholar
  61. 61.
    Winston FK et al (1989) A system to reproduce and quantify the biomechanical environment of the cell. J Appl Physiol 67(1):397–405PubMedCrossRefGoogle Scholar
  62. 62.
    Jones DB et al (1994) Application of homogenous, defined strains to cell cultures. In: Lyall R, el-Haj AJ (eds) Biomechanics and cells. Cambridge University Press, Cambridge, pp 197–219CrossRefGoogle Scholar
  63. 63.
    Nieponice A et al (2007) Mechanical stimulation induces morphological and phenotypic changes in bone marrow-derived progenitor cells within a three-dimensional fibrin matrix. J Biomed Mater Res A 81(3):523–530PubMedCrossRefGoogle Scholar
  64. 64.
    Granet C et al (2001) MAPK and SRC-kinases control EGR-1 and NF-kappa B inductions by changes in mechanical environment in osteoblasts. Biochem Biophys Res Commun 284(3):622–631PubMedCrossRefGoogle Scholar
  65. 65.
    Granet C et al (2002) MAP and src kinases control the induction of AP-1 members in response to changes in mechanical environment in osteoblastic cells. Cell Signal 14(8):679–688PubMedCrossRefGoogle Scholar
  66. 66.
    Bhatt KA et al (2007) Uniaxial mechanical strain: an in vitro correlate to distraction osteogenesis. J Surg Res 143(2):329–336PubMedCrossRefGoogle Scholar
  67. 67.
    Colombo A, Cahill PA, Lally C (2008) An analysis of the strain field in biaxial Flexcell membranes for different waveforms and frequencies. Proc Inst Mech Eng H 222(8):1235–1245PubMedCrossRefGoogle Scholar
  68. 68.
    Brighton CT et al (1991) The proliferative and synthetic response of isolated calvarial bone cells of rats to cyclic biaxial mechanical strain. J Bone Joint Surg Am 73(3):320–331PubMedCrossRefGoogle Scholar
  69. 69.
    Trumbull A, Subramanian G, Yildirim-Ayan E (2016) Mechanoresponsive musculoskeletal tissue differentiation of adipose-derived stem cells. Biomed Eng Online 15:43PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Kariya T et al (2015) Tension force-induced ATP promotes osteogenesis through P2X7 receptor in osteoblasts. J Cell Biochem 116(1):12–21PubMedCrossRefGoogle Scholar
  71. 71.
    Amin S et al (2014) Comparing the effect of equiaxial cyclic mechanical stimulation on GATA4 expression in adipose-derived and bone marrow-derived mesenchymal stem cells. Cell Biol Int 38(2):219–227PubMedCrossRefGoogle Scholar
  72. 72.
    Sun L et al (2016) Effects of mechanical stretch on cell proliferation and matrix formation of mesenchymal stem cell and anterior cruciate ligament fibroblast. Stem Cells Int 2016:9842075PubMedPubMedCentralGoogle Scholar
  73. 73.
    Fermor B et al (1998) Primary human osteoblast proliferation and prostaglandin E2 release in response to mechanical strain in vitro. Bone 22(6):637–643PubMedCrossRefGoogle Scholar
  74. 74.
    Murray DW, Rushton N (1990) The effect of strain on bone cell prostaglandin E2 release: a new experimental method. Calcif Tissue Int 47(1):35–39PubMedCrossRefGoogle Scholar
  75. 75.
    Grabner B et al (1999) A new in vitro system for applying uniaxial strain on cell cultures. Calcif Tissue Int 64(Suppl 1):S114Google Scholar
  76. 76.
    Subramanian G et al (2017) Creating homogenous strain distribution within 3D cell-encapsulated constructs using a simple and cost-effective uniaxial tensile bioreactor: design and validation study. Biotechnol Bioeng 114(8):1878–1887PubMedCrossRefGoogle Scholar
  77. 77.
    Jones DB et al (1991) Biochemical signal transduction of mechanical strain in osteoblast-like cells. Biomaterials 12(2):101–110PubMedCrossRefGoogle Scholar
  78. 78.
    Guo Y et al (2015) Effect of the same mechanical loading on osteogenesis and osteoclastogenesis in vitro. Chin J Traumatol 18(3):150–156PubMedCrossRefGoogle Scholar
  79. 79.
    Tanaka SM (1999) A new mechanical stimulator for cultured bone cells using piezoelectric actuator. J Biomech 32(4):427–430PubMedCrossRefGoogle Scholar
  80. 80.
    Poulin A et al (2016) Dielectric elastomer actuator for mechanical loading of 2D cell cultures. Lab Chip 16(19):3788–3794PubMedCrossRefGoogle Scholar
  81. 81.
    Hughes-Fulford M (2001) Changes in gene expression and signal transduction in microgravity. J Gravit Physiol 8(1):P1–P4PubMedGoogle Scholar
  82. 82.
    Committee on Space Biology and Medicine, C.o.P.S., Mathematics, and Applications, National Research Council, Bone physiology (1998) A strategy for research in space biology and medicine into the next century. The National Academies Press, Washington, DC, pp 80–96Google Scholar
  83. 83.
    Carmeliet G, Vico L, Bouillon R (2001) Space flight: a challenge for normal bone homeostasis. Crit Rev Eukaryot Gene Expr 11(1–3):131–144PubMedGoogle Scholar
  84. 84.
    Nabavi N et al (2011) Effects of microgravity on osteoclast bone resorption and osteoblast cytoskeletal organization and adhesion. Bone 49(5):965–974PubMedCrossRefGoogle Scholar
  85. 85.
    Pardo SJ et al (2005) Simulated microgravity using the random positioning machine inhibits differentiation and alters gene expression profiles of 2T3 preosteoblasts. Am J Physiol Cell Physiol 288(6):C1211–C1221PubMedCrossRefGoogle Scholar
  86. 86.
    Meyers VE et al (2004) Modeled microgravity disrupts collagen I/integrin signaling during osteoblastic differentiation of human mesenchymal stem cells. J Cell Biochem 93(4):697–707PubMedCrossRefGoogle Scholar
  87. 87.
    Meyers VE et al (2005) RhoA and cytoskeletal disruption mediate reduced osteoblastogenesis and enhanced adipogenesis of human mesenchymal stem cells in modeled microgravity. J Bone Miner Res 20(10):1858–1866PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Capulli M et al (2009) Global transcriptome analysis in mouse calvarial osteoblasts highlights sets of genes regulated by modeled microgravity and identifies a “mechanoresponsive osteoblast gene signature”. J Cell Biochem 107(2):240–252PubMedCrossRefGoogle Scholar
  89. 89.
    Vargas GE et al (2009) Biocompatibility and bone mineralization potential of 45S5 bioglass-derived glass-ceramic scaffolds in chick embryos. Acta Biomater 5(1):374–380PubMedCrossRefGoogle Scholar
  90. 90.
    Carmagnola D et al (2008) Oral implants placed in bone defects treated with bio-Oss, Ostim-paste or PerioGlas: an experimental study in the rabbit tibiae. Clin Oral Implants Res 19(12):1246–1253PubMedCrossRefGoogle Scholar
  91. 91.
    Moura J et al (2007) In vitro osteogenesis on a highly bioactive glass-ceramic (biosilicate). J Biomed Mater Res A 82(3):545–557PubMedCrossRefGoogle Scholar
  92. 92.
    Varanasi VG et al (2009) Enhanced osteocalcin expression by osteoblast-like cells (MC3T3-E1) exposed to bioactive coating glass (SiO2-CaO-P2O5-MgO-K2O-Na2O system) ions. Acta Biomater 5(9):3536–3547PubMedCrossRefGoogle Scholar
  93. 93.
    Coathup MJ et al (2017) The effect of increased microporosity on bone formation within silicate-substituted scaffolds in an ovine posterolateral spinal fusion model. J Biomed Mater Res B Appl Biomater 105(4):805–814PubMedCrossRefGoogle Scholar
  94. 94.
    Lanyon LE, Rubin CT (1984) Static vs dynamic loads as an influence on bone remodelling. J Biomech 17(12):897–905PubMedCrossRefGoogle Scholar
  95. 95.
    Rubin CT, Lanyon LE (1985) Regulation of bone mass by mechanical strain magnitude. Calcif Tissue Int 37(4):411–417PubMedCrossRefGoogle Scholar
  96. 96.
    Meakin LB, Price JS, Lanyon LE (2014) The contribution of experimental in vivo models to understanding the mechanisms of adaptation to mechanical loading in bone. Front Endocrinol (Lausanne) 5:154CrossRefGoogle Scholar
  97. 97.
    Smith EL et al (2000) The effects of 20 days of mechanical loading plus PTH on the E-modulus of cow trabecular bone. J Bone Miner Res 15(Suppl 1):S247Google Scholar
  98. 98.
    Walker LM et al (2001) Nicotinic regulation of c-fos and osteopontin expression in human-derived osteoblast-like cells and human trabecular bone organ culture. Bone 28(6):603–608PubMedCrossRefGoogle Scholar
  99. 99.
    El-Haj AJ et al (1990) Cellular responses to mechanical loading in vitro. J Bone Miner Res 5(9):923–932PubMedCrossRefGoogle Scholar
  100. 100.
    Rawlinson SCF et al (1991) Loading-related increases in prostaglandin production in cores of adult canine cancellous bone in vitro: a role for prostacyclin in adaptive bone remodeling? J Bone Miner Res 6(12):1345–1351PubMedCrossRefGoogle Scholar
  101. 101.
    Rawlinson SCF et al (1993) Exogenous prostacyclin, but not prostaglandin E2, produces similar responses in both G6PD activity and RNA production as mechanical loading, and increases IGF-II release, in adult cancellous bone in culture. Calcif Tissue Int 53(5):324–329PubMedCrossRefGoogle Scholar
  102. 102.
    Davies CM et al (2006) Mechanically loaded ex vivo bone culture system 'Zetos': systems and culture preparation. Eur Cell Mater 11:57–75 discussion 75PubMedCrossRefGoogle Scholar
  103. 103.
    David V et al (2008) Ex vivo bone formation in bovine trabecular bone cultured in a dynamic 3D bioreactor is enhanced by compressive mechanical strain. Tissue Eng Part A 14(1):117–126CrossRefGoogle Scholar
  104. 104.
    Endres S et al (2009) Zetos: a culture loading system for trabecular bone. Investigation of different loading signal intensities on bovine bone cylinders. J Musculoskelet Neuronal Interact 9(3):173–183PubMedGoogle Scholar
  105. 105.
    Zong ming W, Jian yu L, Rui xin L, Hao L, Yong G, Lu L, Xin chang Z, Xi zheng Z (2013) Bone formation in rabbit cancellous bone explant culture model is enhanced by mechanical load. Biomed Eng Online 12:35PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Grogan SP et al (2012) Effects of perfusion and dynamic loading on human neocartilage formation in alginate hydrogels. Tissue Eng Part A 18(17–18):1784–1792PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Bouet G et al (2015) Validation of an in vitro 3D bone culture model with perfused and mechanically stressed ceramic scaffold. Eur Cell Mater 29:250–267PubMedCrossRefGoogle Scholar
  108. 108.
    Zaman G et al (1997) Early responses to dynamic strain change and prostaglandins in bone-derived cells in culture. J Bone Miner Res 12(5):769–777PubMedCrossRefGoogle Scholar
  109. 109.
    Zaman G et al (1999) Mechanical strain stimulates nitric oxide production by rapid activation of endothelial nitric oxide synthase in osteocytes. J Bone Miner Res 14(7):1123–1131PubMedCrossRefGoogle Scholar
  110. 110.
    Jessop HL et al (2001) Mechanical strain and estrogen activate estrogen receptor alpha in bone cells. J Bone Miner Res 16(6):1045–1055PubMedCrossRefGoogle Scholar
  111. 111.
    Rawlinson SCF et al (1995) Calvarial and limb bone cells in organ and monolayer culture do not show the same early responses to dynamic mechanical strain. J Bone Miner Res 10(8):1225–1232PubMedCrossRefGoogle Scholar
  112. 112.
    Cheng MZ et al (1997) Enhancement by sex hormones of the osteoregulatory effects of mechanical loading and prostaglandins in explants of rat ulnae. J Bone Miner Res 12(9):1424–1430PubMedCrossRefGoogle Scholar
  113. 113.
    Cheng MZ et al (1996) Mechanical loading and sex hormone interactions in organ cultures of rat ulna. J Bone Miner Res 11(4):502–511PubMedCrossRefGoogle Scholar
  114. 114.
    Rawlinson SCF, Pitsillides AA, Lanyon LE (1996) Involvement of different ion channels in osteoblasts' and osteocytes' early responses to mechanical strain. Bone 19(6):609–614PubMedCrossRefGoogle Scholar
  115. 115.
    Rawlinson SCF, Wheeler-Jones CP, Lanyon LE (2000) Arachidonic acid for loading induced prostacyclin and prostaglandin E(2) release from osteoblasts and osteocytes is derived from the activities of different forms of phospholipase a(2). Bone 27(2):241–247PubMedCrossRefGoogle Scholar
  116. 116.
    Pitsillides AA et al (1999) Bone's early responses to mechanical loading differ in distinct genetic strains of chick: selection for enhanced growth reduces skeletal adaptability. J Bone Miner Res 14(6):980–987PubMedCrossRefGoogle Scholar
  117. 117.
    Dallas SL et al (1993) Early strain-related changes in cultured embryonic chick tibiotarsi parallel those associated with adaptive modeling in vivo. J Bone Miner Res 8(3):251–259PubMedCrossRefGoogle Scholar
  118. 118.
    Zaman G, Dallas SL, Lanyon LE (1992) Cultured embryonic bone shafts show osteogenic responses to mechanical loading. Calcif Tissue Int 51(2):132–136PubMedCrossRefGoogle Scholar
  119. 119.
    Jones DB, Scholubbers JG (1987) Evidence that phospholipase C mediates the mechanical stress effect in bone. Calcif Tissue Int:41Google Scholar
  120. 120.
    Mosley JR et al (1997) Strain magnitude related changes in whole bone architecture in growing rats. Bone 20(3):191–198PubMedCrossRefGoogle Scholar
  121. 121.
    Pitsillides AA et al (1995) Mechanical strain-induced NO production by bone cells: a possible role in adaptive bone (re)modeling? FASEB J 9(15):1614–1622PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Soraia P. Caetano-Silva
    • 1
  • Astrid Novicky
    • 1
  • Behzad Javaheri
    • 1
  • Simon C. F. Rawlinson
    • 2
  • Andrew A. Pitsillides
    • 1
    Email author
  1. 1.Skeletal Biology Group, Comparative Biomedical SciencesThe Royal Veterinary CollegeLondonUK
  2. 2.Barts and The London School of Medicine and Dentistry, Institute of DentistryQueen Mary University of LondonLondonUK

Personalised recommendations