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Mechanobiologie und Knochenstoffwechsel

Klinische Bedeutung für die Frakturbehandlung

Mechanobiology and bone metabolism

Clinical relevance for fracture treatment

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Zusammenfassung

Mechanische Reize beeinflussen signifikant den Knochenmetabolismus und die Frakturheilung. Zahlreiche Studien konnten die Beteiligungen komplexer zellulärer Signaltransduktionswege wie z. B. des Wnt/beta-Catenin-, Bone-morphogenetic-protein(BMP)- oder des Östrogenrezeptor-Signalwegs an der Mechanotransduktion im Knochen belegen. Die Mechanotransduktion wird durch das Alter und Komorbiditäten des Patienten beeinflusst. Die pharmakologische Modulation der Signalwege beeinflusst die Knochenformation und die Mechanosensitivität des Gewebes. Die Kombination von pharmakologischen und biomechanischen Therapieverfahren könnte daher für die Behandlung schlecht heilender Frakturen sinnvoll sein.

Abstract

Mechanical stimuli are known to significantly influence bone metabolism and fracture healing. Various studies have demonstrated the involvement of complex molecular mechanotransduction pathways, such as the Wnt/beta-catenin, bone morphogenetic protein (BMP) and estrogen receptor signaling pathways in mechanotransduction. Mechanotransduction is influenced by aging and the comorbidities of the patient. Pharmacological modulation of signal transduction influences bone formation and the mechanosensitivity of skeletal tissue. The combination of pharmacological and biomechanical therapies may be useful for the treatment of fractures with impaired healing.

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Literatur

  1. Ablove RH, Abrams SS (2015) The use of BMP-2 and screw exchange in the treatment of scaphoid fracture non-union. Hand Surg 20:167–171

    Article  PubMed  Google Scholar 

  2. Agholme F, Isaksson H, Kuhstoss S et al (2011) The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions. Bone 48:988–996

    Article  CAS  PubMed  Google Scholar 

  3. Ai-Aql ZS, Alagl AS, Graves DT et al (2008) Molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis. J Dent Res 87:107–118

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Ali IH, Brazil DP (2014) Bone morphogenetic proteins and their antagonists: current and emerging clinical uses. Br J Pharmacol 171:3620–3632

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Augat P, Margevicius K, Simon J et al (1998) Local tissue properties in bone healing: influence of size and stability of the osteotomy gap. J Orthop Res 16:475–481

    Article  CAS  PubMed  Google Scholar 

  6. Buchtala V (1950) [Present state of ultrasound therapy]. Dia Med 22:2944–2950

    CAS  PubMed  Google Scholar 

  7. Burger EH, Klein-Nulen J (1999) Responses of bone cells to biomechanical forces in vitro. Adv Dent Res 13:93–98

    Article  CAS  PubMed  Google Scholar 

  8. Castillo AB, Triplett JW, Pavalko FM et al (2014) Estrogen receptor-beta regulates mechanical signaling in primary osteoblasts. Am J Physiol Endocrinol Metab 306:E937–E944

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Cheung WH, Chin WC, Qin L et al (2012) Low intensity pulsed ultrasound enhances fracture healing in both ovariectomy-induced osteoporotic and age-matched normal bones. J Orthop Res 30:129–136

    Article  PubMed  Google Scholar 

  10. Chung SL, Leung KS, Cheung WH (2014) Low-magnitude high-frequency vibration enhances gene expression related to callus formation, mineralization and remodeling during osteoporotic fracture healing in rats. J Orthop Res 32:1572–1579

    Article  CAS  PubMed  Google Scholar 

  11. Claes LE, Heigele CA (1999) Magnitudes of local stress and strain along bony surfaces predict the course and type of fracture healing. J Biomech 32:255–266

    Article  CAS  PubMed  Google Scholar 

  12. Claes L, Willie B (2007) The enhancement of bone regeneration by ultrasound. Prog Biophys Mol Biol 93:384–398

    Article  PubMed  Google Scholar 

  13. Claes L, Veeser A, Gockelmann M et al (2009) A novel model to study metaphyseal bone healing under defined biomechanical conditions. Arch Orthop Trauma Surg 129:923–928

    Article  PubMed  Google Scholar 

  14. Claes LE, Heigele CA, Neidlinger-Wilke C et al (1998) Effects of mechanical factors on the fracture healing process. Clin Orthop Relat Res 355:S132–S147

    Article  PubMed  Google Scholar 

  15. Duncan RL, Turner CH (1995) Mechanotransduction and the functional response of bone to mechanical strain. Calcif Tissue Int 57:344–358

    Article  CAS  PubMed  Google Scholar 

  16. Einhorn TA, Gerstenfeld LC (2015) Fracture healing: mechanisms and interventions. Nat Rev Rheumatol 11:45–54

    Article  PubMed Central  PubMed  Google Scholar 

  17. Fan L, Li J, Yu Z et al (2014) The hypoxia-inducible factor pathway, prolyl hydroxylase domain protein inhibitors, and their roles in bone repair and regeneration. Biomed Res Int 2014:239356

    PubMed Central  PubMed  Google Scholar 

  18. Farkash U, Bain O, Gam A et al (2015) Low-intensity pulsed ultrasound for treating delayed union scaphoid fractures: case series. J Orthop Surg Res 10:72

    Article  PubMed Central  PubMed  Google Scholar 

  19. Frost HM (1987) Bone „mass“ and the „mechanostat“: a proposal. Anat Rec 219:1–9

    Article  CAS  PubMed  Google Scholar 

  20. Frost HM (1990) Skeletal structural adaptations to mechanical usage (SATMU): 1. Redefining Wolff’s law: the bone modeling problem. Anat Rec 226:403–413

    Article  CAS  PubMed  Google Scholar 

  21. Fujiwara S, Hamaya E, Sato M et al (2014) Systematic review of raloxifene in postmenopausal Japanese women with osteoporosis or low bone mass (osteopenia). Clin Interv Aging 9:1879–1893

    PubMed Central  CAS  PubMed  Google Scholar 

  22. Gerstenfeld LC, Cullinane DM, Barnes GL et al (2003) Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation. J Cell Biochem 88:873–884

    Article  CAS  PubMed  Google Scholar 

  23. Gong Y, Slee RB, Fukai N et al (2001) LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107:513–523

    Article  CAS  PubMed  Google Scholar 

  24. Haapasalo H, Sievanen H, Kannus P et al (1996) Dimensions and estimated mechanical characteristics of the humerus after long-term tennis loading. J Bone Miner Res 11:864–872

    Article  CAS  PubMed  Google Scholar 

  25. Hauser J, Hauser M, Muhr G et al (2009) Ultrasound-induced modifications of cytoskeletal components in osteoblast-like SAOS-2 cells. J Orthop Res 27:286–294

    Article  PubMed  Google Scholar 

  26. Holguin N, Brodt MD, Sanchez ME et al (2014) Aging diminishes lamellar and woven bone formation induced by tibial compression in adult C57BL/6. Bone 65:83–91

    Article  PubMed Central  PubMed  Google Scholar 

  27. Hsieh YF, Turner CH (2001) Effects of loading frequency on mechanically induced bone formation. J Bone Miner Res 16:918–924

    Article  CAS  PubMed  Google Scholar 

  28. Jagger CJ, Chow JW, Chambers TJ (1996) Estrogen suppresses activation but enhances formation phase of osteogenic response to mechanical stimulation in rat bone. J Clin Invest 98:2351–2357

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Kaspar D, Neidlinger-Wilke C, Holbein O et al (2003) Mitogens are increased in the systemic circulation during bone callus healing. J Orthop Res 21:320–325

    Article  CAS  PubMed  Google Scholar 

  30. Katiyar A, Duncan RL, Sarkar K (2014) Ultrasound stimulation increases proliferation of MC3T3-E1 preosteoblast-like cells. J Ther Ultrasound 2:1

    Article  PubMed Central  PubMed  Google Scholar 

  31. Kopf J, Paarmann P, Hiepen C et al (2014) BMP growth factor signaling in a biomechanical context. Biofactors 40:171–187

    Article  CAS  PubMed  Google Scholar 

  32. Le AX, Miclau T, Hu D et al (2001) Molecular aspects of healing in stabilized and non-stabilized fractures. J Orthop Res 19:78–84

    Article  CAS  PubMed  Google Scholar 

  33. Li CY, Jee WS, Chen JL et al (2003) Estrogen and „exercise“ have a synergistic effect in preventing bone loss in the lumbar vertebra and femoral neck of the ovariectomized rat. Calcif Tissue Int 72:42–49

    Article  CAS  PubMed  Google Scholar 

  34. Liedert A, Kaspar D, Blakytny R et al (2006) Signal transduction pathways involved in mechanotransduction in bone cells. Biochem Biophys Res Commun 349:1–5

    Article  CAS  PubMed  Google Scholar 

  35. Liedert A, Mattausch L, Rontgen V et al (2011) Midkine-deficiency increases the anabolic response of cortical bone to mechanical loading. Bone 48:945–951

    Article  CAS  PubMed  Google Scholar 

  36. Liedert A, Rontgen V, Schinke T et al (2014) Osteoblast-specific Krm2 overexpression and Lrp5 deficiency have different effects on fracture healing in mice. PLoS One 9:e103250

    Article  PubMed Central  PubMed  Google Scholar 

  37. Liedert A, Wagner L, Seefried L et al (2010) Estrogen receptor and Wnt signaling interact to regulate early gene expression in response to mechanical strain in osteoblastic cells. Biochem Biophys Res Commun 394:755–759

    Article  CAS  PubMed  Google Scholar 

  38. Lienau J, Schmidt-Bleek K, Peters A et al (2009) Differential regulation of blood vessel formation between standard and delayed bone healing. J Orthop Res 27:1133–1140

    Article  PubMed  Google Scholar 

  39. Lienau J, Schmidt-Bleek K, Peters A et al (2010) Insight into the molecular pathophysiology of delayed bone healing in a sheep model. Tissue Eng Part A 16:191–199

    Article  CAS  PubMed  Google Scholar 

  40. Liu Y, Wei X, Kuang Y et al (2014) Ultrasound treatment for accelerating fracture healing of the distal radius. A control study. Acta Cir Bras 29:765–770

    Article  PubMed  Google Scholar 

  41. Maintz G (1950) [Animal experiments in the study of the effect of ultrasonic waves on bone regeneration]. Strahlentherapie 82:631–638

    CAS  PubMed  Google Scholar 

  42. Mcbride SH, Silva MJ (2012) Adaptive and injury response of bone to mechanical loading. BoneKey Osteovision 1

  43. Mcclung MR, Grauer A (2014) Romosozumab in postmenopausal women with osteopenia. N Engl J Med 370:1664–1665

    Article  CAS  PubMed  Google Scholar 

  44. Mclean RR (2009) Proinflammatory cytokines and osteoporosis. Curr Osteoporos Rep 7:134–139

    Article  PubMed  Google Scholar 

  45. Mehta M, Strube P, Peters A et al (2010) Influences of age and mechanical stability on volume, microstructure, and mineralization of the fracture callus during bone healing: is osteoclast activity the key to age-related impaired healing? Bone 47:219–228

    Article  CAS  PubMed  Google Scholar 

  46. Nakamura S, Tanaka S (2014) [Biological therapy for osteoporosis]. Clin Calcium 24:919–925

    CAS  PubMed  Google Scholar 

  47. Neidlinger-Wilke C, Stalla I, Claes L et al (1995) Human osteoblasts from younger normal and osteoporotic donors show differences in proliferation and TGF beta-release in response to cyclic strain. J Biomech 28:1411–1418

    Article  CAS  PubMed  Google Scholar 

  48. Nordsletten L (2006) Recent developments in the use of bone morphogenetic protein in orthopaedic trauma surgery. Curr Med Res Opin 22(Suppl 1):S13–S17; S23

    Article  CAS  PubMed  Google Scholar 

  49. Norvell SM, Alvarez M, Bidwell JP et al (2004) Fluid shear stress induces beta-catenin signaling in osteoblasts. Calcif Tissue Int 75:396–404

    Article  CAS  PubMed  Google Scholar 

  50. Ode A, Duda GN, Geissler S et al (2014) Interaction of age and mechanical stability on bone defect healing: an early transcriptional analysis of fracture hematoma in rat. PLoS One 9:e106462

    Article  PubMed Central  PubMed  Google Scholar 

  51. Olkku A, Leskinen JJ, Lammi MJ et al (2010) Ultrasound-induced activation of Wnt signaling in human MG-63 osteoblastic cells. Bone 47:320–330

    Article  CAS  PubMed  Google Scholar 

  52. Padilla F, Puts R, Vico L et al (2014) Stimulation of bone repair with ultrasound: a review of the possible mechanic effects. Ultrasonics 54:1125–1145

    Article  CAS  PubMed  Google Scholar 

  53. Pauwels F (1960) Eine neue Theorie über den Einfluß mechanischer Reize auf die Differenzierung der Stützgewebe. Z Anat Entwicklungsgeschichte 121:478–515

    Article  CAS  Google Scholar 

  54. Perren SM, Rahn BA (1980) Biomechanics of fracture healing. Can J Surg 23:228–232

    CAS  PubMed  Google Scholar 

  55. Rauner M, Sipos W, Pietschmann P (2008) Age-dependent Wnt gene expression in bone and during the course of osteoblast differentiation. Age (Dordr) 30:273–282

    Article  Google Scholar 

  56. Russell SJ, Kahn CR (2007) Endocrine regulation of ageing. Nat Rev Mol Cell Biol 8:681–691

    Article  CAS  PubMed  Google Scholar 

  57. Salisbury Palomares KT, Gerstenfeld LC, Wigner NA et al (2010) Transcriptional profiling and biochemical analysis of mechanically induced cartilaginous tissues in a rat model. Arthritis Rheum 62:1108–1118

    Article  PubMed Central  PubMed  Google Scholar 

  58. Sawakami K, Robling AG, Ai M et al (2006) The Wnt co-receptor LRP5 is essential for skeletal mechanotransduction but not for the anabolic bone response to parathyroid hormone treatment. J Biol Chem 281:23698–23711

    Article  CAS  PubMed  Google Scholar 

  59. Saxon LK, Turner CH (2005) Estrogen receptor beta: the antimechanostat? Bone 36:185–192

    Article  CAS  PubMed  Google Scholar 

  60. Spatz JM, Ellman R, Cloutier AM et al (2013) Sclerostin antibody inhibits skeletal deterioration due to reduced mechanical loading. J Bone Miner Res 28:865–874

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Sterck JG, Klein-Nulend J, Lips P et al (1998) Response of normal and osteoporotic human bone cells to mechanical stress in vitro. Am J Physiol 274:E1113–E1120

    CAS  PubMed  Google Scholar 

  62. Strube P, Sentuerk U, Riha T et al (2008) Influence of age and mechanical stability on bone defect healing: age reverses mechanical effects. Bone 42:758–764

    Article  PubMed  Google Scholar 

  63. Stuermer EK, Komrakova M, Sehmisch S et al (2014) Whole body vibration during fracture healing intensifies the effects of estradiol and raloxifene in estrogen-deficient rats. Bone 64:187–194

    Article  CAS  PubMed  Google Scholar 

  64. Temiyasathit S, Jacobs CR (2010) Osteocyte primary cilium and its role in bone mechanotransduction. Ann N Y Acad Sci 1192:422–428

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Tu X, Rhee Y, Condon KW et al (2012) Sost downregulation and local Wnt signaling are required for the osteogenic response to mechanical loading. Bone 50:209–217

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Turner RT (1999) Mechanical signaling in the development of postmenopausal osteoporosis. Lupus 8:388–392

    Article  CAS  PubMed  Google Scholar 

  67. Uzer G, Pongkitwitoon S, Ete Chan M et al (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 Central  PubMed  Google Scholar 

  68. Uzer G, Thompson WR, Sen B et al (2015) Cell mechanosensitivity to extremely low-magnitude signals is enabled by a LINCed Nucleus. Stem Cells 33:2063–2076

    Article  PubMed Central  PubMed  Google Scholar 

  69. Von Stengel S, Kemmler W, Engelke K et al (2011) Effects of whole body vibration on bone mineral density and falls: results of the randomized controlled ELVIS study with postmenopausal women. Osteoporos Int 22:317–325

    Article  Google Scholar 

  70. Watabe H, Furuhama T, Tani-Ishii N et al (2011) Mechanotransduction activates alpha(5)beta(1) integrin and PI3K/Akt signaling pathways in mandibular osteoblasts. Exp Cell Res 317:2642–2649

    Article  CAS  PubMed  Google Scholar 

  71. Wehrle E, Liedert A, Heilmann A et al (2015) The impact of low-magnitude high-frequency vibration on fracture healing is profoundly influenced by the oestrogen status in mice. Dis Model Mech 8:93–104

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Wehrle E, Wehner T, Heilmann A et al (2014) Distinct frequency dependent effects of whole-body vibration on non-fractured bone and fracture healing in mice. J Orthop Res 32:1006–1013

    Article  PubMed  Google Scholar 

  73. Weinbaum S, Cowin SC, Zeng Y (1994) A model for the excitation of osteocytes by mechanical loading-induced bone fluid shear stresses. J Biomech 27:339–360

    Article  CAS  PubMed  Google Scholar 

  74. Windahl SH, Saxon L, Borjesson AE et al (2013) Estrogen receptor-alpha is required for the osteogenic response to mechanical loading in a ligand-independent manner involving its activation function 1 but not 2. J Bone Miner Res 28:291–301

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. Wolff J (1892) Das Gesetz der Transformation der Knochen. A. Hirschwald, Berlin

  76. Xie L, Rubin C, Judex S (2008) Enhancement of the adolescent murine musculoskeletal system using low-level mechanical vibrations. J Appl Physiol (1985) 104:1056–1062

    Article  Google Scholar 

  77. Yellowley C (2013) CXCL12/CXCR4 signaling and other recruitment and homing pathways in fracture repair. Bonekey Rep 2:300

    Article  PubMed Central  PubMed  Google Scholar 

  78. Yu YY, Lieu S, Lu C et al (2010) Immunolocalization of BMPs, BMP antagonists, receptors, and effectors during fracture repair. Bone 46:841–851

    Article  CAS  PubMed  Google Scholar 

  79. Zaman G, Jessop HL, Muzylak M et al (2006) Osteocytes use estrogen receptor alpha to respond to strain but their ERalpha content is regulated by estrogen. J Bone Miner Res 21:1297–1306

    Article  CAS  PubMed  Google Scholar 

  80. Zura R, Della Rocca GJ, Mehta S et al (2015) Treatment of chronic (> 1 year) fracture nonunion: heal rate in a cohort of 767 patients treated with low-intensity pulsed ultrasound (LIPUS). Injury 46(10):2036–2041

    Article  PubMed  Google Scholar 

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  1. Institut für Unfallchirurgische Forschung und Biomechanik, Universitätsklinikum Ulm, Helmholtzstraße 14, 89081, Ulm, Deutschland

    M. Haffner-Luntzer, A. Liedert & A. Ignatius

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  1. M. Haffner-Luntzer
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M. Haffner-Luntzer, A. Liedert und A. Ignatius geben an, dass kein Interessenkonflikt besteht.

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Haffner-Luntzer, M., Liedert, A. & Ignatius, A. Mechanobiologie und Knochenstoffwechsel. Unfallchirurg 118, 1000–1006 (2015). https://doi.org/10.1007/s00113-015-0102-z

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