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Effect of low-intensity whole-body vibration on bone defect repair and associated vascularization in mice

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Abstract

Low-intensity whole-body vibration (LIWBV) may stimulate bone healing, but the involvement of vascular ingrowth, which is essential for bone regeneration, has not been well examined. We thus investigated the LIWBV effect on vascularization during early-stage bone healing. Mice aged 13 weeks were subjected to cortical drilling on tibial bone. Two days after surgery (day 0), mice were exposed daily to sine-wave LIWBV at 30 Hz and 0.1 g peak-to-peak acceleration for 20 min/day (Vib) or were sham-treated (sham). Following vascular casting with a zirconium-based contrast agent on days 6, 9, or 12 and sacrifice, vascular and bone images were obtained by K-edge subtraction micro-CT using synchrotron lights. Bone regeneration advanced more in the Vib group from days 9 to 12. The vascular volume fraction decreased from days 6 to 9 in both groups; however, from days 9 to 12, it was increased in shams, while it stabilized in the Vib group. The vascular volume fraction tended to be or was smaller in the Vib group on days 6 and 12. The vessel number density was higher on day 9 but lower on day 12 in the Vib group. These results suggest that the LIWBV-promoted bone repair is associated with the modulation of vascularization, but additional studies are needed to determine the causality of this association.

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References

  1. Bacabac RG, Smit TH, Van Loon JJ, Doulabi BZ, Helder M, Klein-Nulend J (2006) Bone cell responses to high-frequency vibration stress: does the nucleus oscillate within the cytoplasm? FASEB J 20:858–864

    Article  CAS  PubMed  Google Scholar 

  2. Baek K, Barlow A, Allen M, Bloomfield S (2008) Food restriction and simulated microgravity: effects on bone and serum leptin. J Appl Physiol 104:1086–1093

    Article  CAS  PubMed  Google Scholar 

  3. Boerckel JD, Kolambkar YM, Stevens HY, Lin AS, Dupont KM, Guldberg RE (2012) Effects of in vivo mechanical loading on large bone defect regeneration. J Orthop Res 30:1067–1075

    Article  PubMed  Google Scholar 

  4. Boerckel JD, Uhrig BA, Willett NJ, Huebsch N, Guldberg RE (2011) Mechanical regulation of vascular growth and tissue regeneration in vivo. Proc Natl Acad Sci U S A 108:E674–E680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bosco C, Iacovelli M, Tsarpela O, Cardinale M, Bonifazi M, Tihanyi J, Viru M, De Lorenzo A, Viru A (2000) Hormonal responses to whole-body vibration in men. Eur J Appl Physiol 81:449–454

    Article  CAS  PubMed  Google Scholar 

  6. Brotto M, Bonewald L (2015) Bone and muscle: interactions beyond mechanical. Bone 80:109–114

    Article  PubMed  PubMed Central  Google Scholar 

  7. Carano RA, Filvaroff EH (2003) Angiogenesis and bone repair. Drug Discov Today 8:980–989

    Article  CAS  PubMed  Google Scholar 

  8. Cheung WH, Sun MH, Zheng YP, Chu WC, Leung AH, Qin L, Wei FY, Leung KS (2012) Stimulated angiogenesis for fracture healing augmented by low-magnitude, high-frequency vibration in a rat model-evaluation of pulsed-wave doppler, 3-D power Doppler ultrasonography and micro-CT microangiography. Ultrasound Med Biol 38:2120–2129

    Article  PubMed  Google Scholar 

  9. Christiansen BA, Silva MJ (2006) The effect of varying magnitudes of whole-body vibration on several skeletal sites in mice. Ann Biomed Eng 34:1149–1156

    Article  PubMed  Google Scholar 

  10. Dan P, Velot É, Decot V, Menu P (2015) The role of mechanical stimuli in the vascular differentiation of mesenchymal stem cells. J Cell Sci 128:2415–2422

    Article  CAS  PubMed  Google Scholar 

  11. Doube M, Kłosowski MM, Arganda-Carreras I, Cordelières FP, Dougherty RP, Jackson JS, Schmid B, Hutchinson JR, Shefelbine SJ (2010) BoneJ: free and extensible bone image analysis in ImageJ. Bone 47:1076–1079

    Article  PubMed  PubMed Central  Google Scholar 

  12. Drake CJ, Little CD (1995) Exogenous vascular endothelial growth factor induces malformed and hyperfused vessels during embryonic neovascularization. Proc Natl Acad Sci U S A 92:7657–7661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Edwards JH, Reilly GC (2015) Vibration stimuli and the differentiation of musculoskeletal progenitor cells: review of results in vitro and in vivo. World J Stem Cells 7:568–582

    Article  PubMed  PubMed Central  Google Scholar 

  14. Ford NL, Thornton MM, Holdsworth DW (2003) Fundamental image quality limits for microcomputed tomography in small animals. Med Phys 30:2869–2877

    Article  CAS  PubMed  Google Scholar 

  15. Garcia P, Pieruschka A, Klein M, Tami A, Histing T, Holstein JH, Scheuer C, Pohlemann T, Menger MD (2012) Temporal and spatial vascularization patterns of unions and nonunions: role of vascular endothelial growth factor and bone morphogenetic proteins. J Bone Joint Surg Am 94:49–58

    Article  CAS  PubMed  Google Scholar 

  16. Garman R, Gaudette G, Donahue LR, Rubin C, Judex S (2007) Low-level accelerations applied in the absence of weight bearing can enhance trabecular bone formation. J Orthop Res 25:732–740

    Article  PubMed  Google Scholar 

  17. Garman R, Rubin C, Judex S (2007) Small oscillatory accelerations, independent of matrix deformations, increase osteoblast activity and enhance bone morphology. PLoS One 2:e653

    Article  PubMed  PubMed Central  Google Scholar 

  18. Gill TM, Murphy TE, Gahbauer EA, Allore HG (2013) Association of injurious falls with disability outcomes and nursing home admissions in community-living older persons. Am J Epidemiol 178:418–425

    Article  PubMed  PubMed Central  Google Scholar 

  19. Groothuis A, Duda G, Wilson C, Thompson M, Hunter M, Simon P, Bail H, van Scherpenzeel K, Kasper G (2010) Mechanical stimulation of the pro-angiogenic capacity of human fracture haematoma: involvement of VEGF mechano-regulation. Bone 47:438–444

    Article  CAS  PubMed  Google Scholar 

  20. Han Y, Cowin SC, Schaffler MB, Weinbaum S (2004) Mechanotransduction and strain amplification in osteocyte cell processes. Proc Natl Acad Sci U S A 101:16689–16694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hausman MR, Schaffler MB, Majeska RJ (2001) Prevention of fracture healing in rats by an inhibitor of angiogenesis. Bone 29:560–564

    Article  CAS  PubMed  Google Scholar 

  22. He YX, Zhang G, Pan XH, Liu Z, Zheng LZ, Chan CW, Lee KM, Cao YP, Li G, Wei L, Hung LK, Leung KS, Qin L (2011) Impaired bone healing pattern in mice with ovariectomy-induced osteoporosis: a drill-hole defect model. Bone 48:1388–1400

    Article  PubMed  Google Scholar 

  23. Hung WW, Egol KA, Zuckerman JD, Siu AL (2012) Hip fracture management: tailoring care for the older patient. JAMA 307:2185–2194

    Article  CAS  PubMed  Google Scholar 

  24. Hwang SJ, Lublinsky S, Seo YK, Kim IS, Judex S (2009) Extremely small-magnitude accelerations enhance bone regeneration: a preliminary study. Clin Orthop Relat Res 467:1083–1091

    Article  PubMed  Google Scholar 

  25. Judex S, Donahue LR, Rubin C (2002) Genetic predisposition to low bone mass is paralleled by an enhanced sensitivity to signals anabolic to the skeleton. FASEB J 16:1280–1282

    CAS  PubMed  Google Scholar 

  26. Kamel HK, Iqbal MA, Mogallapu R, Maas D, Hoffmann RG (2003) Time to ambulation after hip fracture surgery: relation to hospitalization outcomes. J Gerontol A Biol Sci Med Sci 58:1042–1045

    Article  PubMed  Google Scholar 

  27. Komatsu DE, Hadjiargyrou M (2004) Activation of the transcription factor HIF-1 and its target genes, VEGF, HO-1, iNOS, during fracture repair. Bone 34:680–688

    Article  CAS  PubMed  Google Scholar 

  28. Kusumbe AP, Ramasamy SK, Adams RH (2014) Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature 507:323–328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Leung KS, Shi HF, Cheung WH, Qin L, Ng WK, Tam KF, Tang N (2009) Low-magnitude high-frequency vibration accelerates callus formation, mineralization, and fracture healing in rats. J Orthop Res 27:458–465

    Article  PubMed  Google Scholar 

  30. Lin GL, Hankenson KD (2011) Integration of BMP, Wnt, and notch signaling pathways in osteoblast differentiation. J Cell Biochem 112:3491–3501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Maes C, Kobayashi T, Selig MK, Torrekens S, Roth SI, Mackem S, Carmeliet G, Kronenberg HM (2010) Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels. Dev Cell 19:329–344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Maes F, Collignon A, Vandermeulen D, Marchal G, Suetens P (1997) Multimodality image registration by maximization of mutual information. IEEE Trans Med Imaging 16:187–198

    Article  CAS  PubMed  Google Scholar 

  33. Matsumoto T, Goto D, Sato S (2013) Subtraction micro-computed tomography of angiogenesis and osteogenesis during bone repair using synchrotron radiation with a novel contrast agent. Lab Investig 93:1054–1063

    Article  CAS  PubMed  Google Scholar 

  34. Matsumoto T, Itamochi S, Hashimoto Y (2016) Effect of concurrent use of whole-body vibration and parathyroid hormone on bone structure and material properties of ovariectomized mice. Calcif Tissue Int 98:520–529

    Article  CAS  PubMed  Google Scholar 

  35. Matsumoto T, Sato S (2015) Stimulating angiogenesis mitigates the unloading-induced reduction in osteogenesis in early-stage bone repair in rats. Physiol Rep 3:e12335

    Article  PubMed  PubMed Central  Google Scholar 

  36. Maul TM, Chew DW, Nieponice A, Vorp DA (2011) Mechanical stimuli differentially control stem cell behavior: morphology, proliferation, and differentiation. Biomech Model Mechanobiol 10:939–953

    Article  PubMed  PubMed Central  Google Scholar 

  37. McCabe N, Androjna C, Hill E, Globus R, Midura R (2013) Simulated microgravity alters the expression of key genes involved in fracture healing. Acta Astronaut 92:65–72

    Article  CAS  Google Scholar 

  38. Monfoulet L, Rabier B, Chassande O, Fricain JC (2010) Drilled hole defects in mouse femur as models of intramembranous cortical and cancellous bone regeneration. Calcif Tissue Int 86:72–81

    Article  CAS  PubMed  Google Scholar 

  39. Moore D, Leblanc C, Muller R, Crisco J, Ehrlich M (2003) Physiologic weight-bearing increases new vessel formation during distraction osteogenesis: a micro-tomographic imaging study. J Orthop Res 21:489–496

    Article  PubMed  Google Scholar 

  40. Muir J, Kiel DP, Rubin CT (2013) Safety and severity of accelerations delivered from whole body vibration exercise devices to standing adults. J Sci Med Sport 16:526–531

    Article  PubMed  PubMed Central  Google Scholar 

  41. Mundy GR, Chen D, Zhao M, Dallas S, Xu C, Harris S (2001) Growth regulatory factors and bone. Rev Endocr Metab Disord 2:105–115

    Article  CAS  PubMed  Google Scholar 

  42. Murfee WL, Hammett LA, Evans C, Xie L, Squire M, Rubin C, Judex S, Skalak TC (2005) High-frequency, low-magnitude vibrations suppress the number of blood vessels per muscle fiber in mouse soleus muscle. J Appl Physiol (1985) 98:2376–2380

    Article  Google Scholar 

  43. Omar H, Shen G, Jones AS, Zoellner H, Petocz P, Darendeliler MA (2008) Effect of low magnitude and high frequency mechanical stimuli on defects healing in cranial bones. J Oral Maxillofac Surg 66:1104–1111

    Article  PubMed  Google Scholar 

  44. Otsuki T, Takanami Y, Aoi W, Kawai Y, Ichikawa H, Yoshikawa T (2008) Arterial stiffness acutely decreases after whole-body vibration in humans. Acta Physiol (Oxf) 194:189–194

    Article  CAS  Google Scholar 

  45. Pal N (1996) On minimum cross-entropy thresholding. Pattern Recogn 29:575–580

    Article  Google Scholar 

  46. Pasqualini M, Lavet C, Elbadaoui M, Vanden-Bossche A, Laroche N, Gnyubkin V, Vico L (2013) Skeletal site-specific effects of whole body vibration in mature rats: from deleterious to beneficial frequency-dependent effects. Bone 55:69–77

    Article  PubMed  Google Scholar 

  47. Peng H, Wright V, Usas A, Gearhart B, Shen HC, Cummins J, Huard J (2002) Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4. J Clin Invest 110:751–759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Robling AG, Turner CH (2002) Mechanotransduction in bone: genetic effects on mechanosensitivity in mice. Bone 31:562–569

    Article  CAS  PubMed  Google Scholar 

  49. Rubin C, Pope M, Fritton JC, Magnusson M, Hansson T, McLeod K (2003) Transmissibility of 15-hertz to 35-hertz vibrations to the human hip and lumbar spine: determining the physiologic feasibility of delivering low-level anabolic mechanical stimuli to skeletal regions at greatest risk of fracture because of osteoporosis. Spine (Phila Pa 1976) 28:2621–2627

    Article  Google Scholar 

  50. Schipani E, Maes C, Carmeliet G, Semenza GL (2009) Regulation of osteogenesis-angiogenesis coupling by HIFs and VEGF. J Bone Miner Res 24:1347–1353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Stewart JM, Karman C, Montgomery LD, McLeod KJ (2005) Plantar vibration improves leg fluid flow in perimenopausal women. Am J Phys Regul Integr Comp Phys 288:R623–R629

    CAS  Google Scholar 

  52. Street J, Bao M, de Guzman L, Bunting S, Peale FV, Ferrara N, Steinmetz H, Hoeffel J, Cleland JL, Daugherty A, van Bruggen N, Redmond HP, Carano RA, Filvaroff EH (2002) Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci U S A 99:9656–9661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Stuermer EK, Komrakova M, Werner C, Wicke M, Kolios L, Sehmisch S, Tezval M, Utesch C, Mangal O, Zimmer S, Dullin C, Stuermer KM (2010) Musculoskeletal response to whole-body vibration during fracture healing in intact and ovariectomized rats. Calcif Tissue Int 87:168–180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Szczesny SE, Lee CS, Soslowsky LJ (2010) Remodeling and repair of orthopedic tissue: role of mechanical loading and biologics. Am J Orthop 39:525–530

    PubMed  Google Scholar 

  55. Towler DA (2008) The osteogenic-angiogenic interface: novel insights into the biology of bone formation and fracture repair. Curr Osteoporos Rep 6:67–71

    Article  PubMed  Google Scholar 

  56. Usui Y, Zerwekh JE, Vanharanta H, Ashman RB, Mooney V (1989) Different effects of mechanical vibration on bone ingrowth into porous hydroxyapatite and fracture healing in a rabbit model. J Orthop Res 7:559–567

    Article  CAS  PubMed  Google Scholar 

  57. Uzer G, Pongkitwitoon S, Ete Chan M, Judex S (2013) Vibration induced osteogenic commitment of mesenchymal stem cells is enhanced by cytoskeletal remodeling but not fluid shear. J Biomech 46:2296–2302

    Article  PubMed  PubMed Central  Google Scholar 

  58. Uzer G, Thompson WR, Sen B, Xie Z, Yen SS, Miller S, Bas G, Styner M, Rubin CT, Judex S, Burridge K, Rubin J (2015) Cell mechanosensitivity to extremely low-magnitude signals is enabled by a LINCed nucleus. Stem Cells 33:2063–2076

    Article  PubMed  PubMed Central  Google Scholar 

  59. Wagatsuma A (2008) Effect of hindlimb unweighting on expression of hypoxia-inducible factor-1alpha vascular endothelial growth factor, angiopoietin, and their receptors in mouse skeletal muscle. Physiol Res 57:613–620

    CAS  PubMed  Google Scholar 

  60. Wohl GR, Towler DA, Silva MJ (2009) Stress fracture healing: fatigue loading of the rat ulna induces upregulation in expression of osteogenic and angiogenic genes that mimic the intramembranous portion of fracture repair. Bone 44:320–330

    Article  CAS  PubMed  Google Scholar 

  61. Wong LC, Chiu WK, Russ M, Liew S (2012) Review of techniques for monitoring the healing fracture of bones for implementation in an internally fixated pelvis. Med Eng Phys 34:140–152

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors are indebted to Shota Sato (Osaka University Graduate School of Engineering Science) for his assistance with image processing and analysis. This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of the Japanese government (grant nos. 24650265 and 26282120). The synchrotron radiation experiments were performed at SPring-8 with the approval of the Japan Synchrotron Radiation Research Institute (proposal no. 2013A1667).

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  1. Department of Mechanical Science, Tokushima University Graduate School of Science and Technology, 2-1 Minamijosanjima, Tokushima, 770-8506, Japan

    Takeshi Matsumoto

  2. Department of Mechanical Science and Bioengineering, Osaka University Graduate School of Engineering Science, 1-3 Machikaneyama, Toyonaka, 560-8531, Japan

    Takeshi Matsumoto & Daichi Goto

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  1. Takeshi Matsumoto
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Correspondence to Takeshi Matsumoto.

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Experiments were conducted in accordance with the guiding principles of the American Physiological Society and with the approval of the Animal Research Committee of Osaka University Graduate School of Engineering Science.

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Matsumoto, T., Goto, D. Effect of low-intensity whole-body vibration on bone defect repair and associated vascularization in mice. Med Biol Eng Comput 55, 2257–2266 (2017). https://doi.org/10.1007/s11517-017-1664-4

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