Die Maus als Tiermodell in der Frakturheilungsforschung

Zusammenfassung

Mausmodelle werden mehr und mehr für die Frakturheilungsforschung eingesetzt. Es stehen zahlreiche verschiedene Mausstämme zur Verfügung. Zu beachten ist jedoch, dass sich die verschiedenen Mausstämme zum Teil erheblich bezüglich Knochenphänotyp und Heilungscharakteristik unterscheiden. Zudem sind auch in der Maus standardisierte und mechanisch kontrollierte Frakturmodelle obligatorisch, da die mechanischen Bedingungen das Versuchsergebnis erheblich be-einflussen. Die standardisierte Frakturfixation ist in der Maus aufgrund der geringen Skelettgröße eine technische Herausforderung. Inzwischen gibt es jedoch eine Reihe kommerziell verfügbarer Osteosynthesesysteme für das Mäusefemur, mit denen kontrollierte Studien möglich sind. Es können Marknägel, Platten oder Fixateur externe verwendet werden. Alle Systeme haben verschiedene Vor- und Nachteile, die bei der Auswahl des Versuchsdesigns für die jeweilige Fragestellung berücksichtigt werden müssen. Durch diese methodischen Fortschritte werden genetisch veränderte Mausmodelle für die Forschung nutzbar gemacht. Durch Ausschalten, Über- oder sogar ektopische Expression eines einzelnen Gens in der Maus kann nicht nur seine physiologische bzw. pathologische Bedeutung, sondern auch ein möglicher pharmakologischer Effekt überprüft werden. Mausmodelle stellen damit ein sehr wertvolles Werkzeug für die Frakturheilungsforschung dar, wenn auch die Bedeutung der gewonnenen Erkenntnisse im Großtiermodell und im Menschen überprüft werden muss.

Summary

Mouse models are increasingly used for fracture healing studies. Many inbred strains are available. The inbred strains significantly differ in bone phenotype and healing characteristics. Furthermore, also in mice standardized and mechanically controlled fracture healing models are obligate, because the mechanical conditions considerably influence the fracture healing outcome. Standardized fracture fixation techniques for the mouse are a technical challenge due to the small skeleton. However, in the meantime several different fixation devices are commercially available for the mouse femur allowing controlled fracture healing studies. Intramedullary nails, plates and external fixators can be used. All devices have various advantages and disadvantages, which should be regarded, dependeding on the scientific question to be answered. By these methodical improvements genetically modified mouse models can be used for fracture healing research. By deletion, over-expression or ectopic expression of a gene of interest its physiological or pathological role or its pharmacological effect can be investigated. Therefore, mouse models represent a very worthwhile tool for fracture healing research, even if the results have to be checked in large animal models and in human.

Schlüsselwörter

Mausmodelle - Frakturheilung - Frakturmodelle

Keywords

Mouse model - fracture healing - fracture model

• Literatur

• 1 Akhter MP, Cullen DM, Pedersen EA. et al. Bone response to in vivo mechanical loading in two breeds of mice. Calcif Tissue Int 1998; 63 (05) 442-449.
• 2 Akhter MP, Fan Z, Rho JY. Bone intrinsic material properties in three inbred mouse strains. Calcif Tissue Int 2004; 75 (05) 416-420.
• 3 Amblard D, Lafage-Proust MH, Laib A. et al. Tail suspension induces bone loss in skeletally mature mice in the C57BL/6J strain but not in the C3H/HeJ strain. J Bone Miner Res 2003; 18 (03) 561-569.
• 4 Augat P, Burger J, Schorlemmer S. et al. Shear movement at the fracture site delays healing in a diaphyseal fracture model. J Orthop Res 2003; 21 (06) 1011-1017.
• 5 Augat P, Simon U, Liedert A, Claes L. Mechanics and mechano-biology of fracture healing in normal and osteoporotic bone. Osteoporos Int 2005; 16 (Suppl. 02) S36-S43.
• 6 Beamer WG, Donahue LR, Rosen CJ, Baylink DJ. Genetic variability in adult bone density among inbred strains of mice. Bone 1996; 18 (05) 397-403.
• 7 Bhandari M, Guyatt G, Tornetta 3rd P. et al. Randomized trial of reamed and unreamed intramedullary nailing of tibial shaft fractures. J Bone Joint Surg Am 2008; 90 (12) 2567-2578.
• 8 Bonnarens F, Einhorn TA. Production of a standard closed fracture in laboratory animal bone. J Orthop Res 1984; 02 (01) 97-101.
• 9 Bouxsein ML, Myers KS, Shultz KL. et al. Ovariectomy-induced bone loss varies among inbred strains of mice. J Bone Miner Res 2005; 20 (07) 1085-1092.
• 10 Claes L, Augat P, Suger G, Wilke HJ. Influence of size and stability of the osteotomy gap on the success of fracture healing. J Orthop Res 1997; 15 (04) 577-584.
• 11 Claes L, Veeser A, Gockelmann M. et al. A novel model to study metaphyseal bone healing under defined biomechanical conditions. Arch Orthop Trauma Surg 2009; 129 (07) 923-928.
• 12 Claes L, Reusch M, Gockelmann M. et al. Metaphyseal fracture healing follows similar biomechanical rules as diaphyseal healing. J Orthop Res. 2010 Sep 29. [Epub ahead of print].
• 13 Claes LE, Heigele CA, Neidlinger-Wilke C. et al. Effects of mechanical factors on the fracture healing process. Clin Orthop 1998; (355 Suppl): S132-S147.
• 14 Claes LE, Heigele CA. Magnitudes of local stress and strain along bony surfaces predict the course and type of fracture healing. J Biomech 1999; 32 (03) 255-266.
• 15 Connolly CK, Li G, Bunn JR. et al. A reliable externally fixated murine femoral fracture model that accounts for variation in movement between animals. J Orthop Res 2003; 21 (05) 843-849.
• 16 Duda GN, Eckert-Hubner K, Sokiranski R. et al. Analysis of inter-fragmentary movement as a function of musculoskeletal loading conditions in sheep. J Biomech 1998; 31 (03) 201-210.
• 17 Epari DR, Kassi JP, Schell H, Duda GN. Timely fracture-healing requires optimization of axial fixation stability. J Bone Joint Surg Am 2007; 89 (07) 1575-1585.
• 18 Gerstenfeld LC, Cho TJ, Kon T. et al. Impaired fracture healing in the absence of TNF-alpha signaling: the role of TNF-alpha in endochondral cartilage resorption. J Bone Miner Res 2003; 18 (09) 1584-1592.
• 19 Gerstenfeld LC, McLean J, Healey DS. et al. Genetic variation in the structural pattern of osteoclast activity during post-natal growth of mouse femora. Bone 2010; 46 (06) 1546-1554.
• 20 Grongroft I, Heil P, Matthys R. et al. Fixation compliance in a mouse osteotomy model induces two different processes of bone healing but does not lead to delayed union. J Biomech 2009; 42 (13) 2089-2096.
• 21 Gunther T, Schinke T. Mouse genetics have uncovered new paradigms in bone biology. Trends Endocrinol Metab 2000; 11 (05) 189-193.
• 22 Histing T, Holstein JH, Garcia P. et al. Ex vivo analysis of rotational stiffness of different osteosynthesis techniques in mouse femur fracture. J Orthop Res 2009; 27 (09) 1152-1156.
• 23 Histing T, Garcia P, Matthys R. et al. An internal locking plate to study intramembranous bone healing in a mouse femur fracture model. J Orthop Res 2010; 28 (03) 397-402.
• 24 Holstein JH, Menger MD, Culemann U. et al. Development of a locking femur nail for mice. J Biomech 2007; 40 (01) 215-219.
• 25 Holstein JH, Matthys R, Histing T. et al. Development of a stable closed femoral fracture model in mice. J Surg Res 2009; 153 (01) 71-75.
• 26 Jepsen KJ, Pennington DE, Lee YL. et al. Bone brittleness varies with genetic background in A/J and C57BL/6J inbred mice. J Bone Miner Res 2001; 16 (10) 1854-1862.
• 27 Jepsen KJ, Price C, Silkman LJ. et al. Genetic variation in the patterns of skeletal progenitor cell differentiation and progression during endochondral bone formation affects the rate of fracture healing. J Bone Miner Res 2008; 23 (08) 1204-1216.
• 28 Li X, Gu W, Masinde G. et al. Genetic variation in bone-regenerative capacity among inbred strains of mice. Bone 2001; 29 (02) 134-140.
• 29 Lovell DP, Johnson FM. Quantitative genetic variation in the skeleton of the mouse. I. Variation between inbred strains. Genet Res 1983; 42 (02) 169-182.
• 30 Lovell DP, Johnson FM, Willis DB. Quantitative genetic variation in the skeleton of the mouse: II. Description of variation within and between inbred strains. Am J Anat 1986; 176 (03) 287-303.
• 31 Manigrasso MB, O’Connor JP. Characterization of a closed femur fracture model in mice. J Orthop Trauma 2004; 18 (10) 687-695.
• 32 Manigrasso MB, O’Connor JP. Comparison of fracture healing among different inbred mouse strains. Calcif Tissue Int 2008; 82 (06) 465-474.
• 33 Park SH, O’Connor K, Sung R. et al. Comparison of healing process in open osteotomy model and closed fracture model. J Orthop Trauma 1999; 13 (02) 114-120.
• 34 Pogoda P, Priemel M, Schilling AF. et al. Mouse models in skeletal physiology and osteoporosis: experiences and data on 14,839 cases from the Hamburg Mouse Archives. J Bone Miner Metab 2005; 23 (Suppl): 97-102.
• 35 Price C, Herman BC, Lufkin T. et al. Genetic variation in bone growth patterns defines adult mouse bone fragility. J Bone Miner Res 2005; 20 (11) 1983-1991.
• 36 Rontgen V, Blakytny R, Matthys R. et al. Fracture healing in mice under controlled rigid and flexible conditions using an adjustable external fixator. J Orthop Res 2010; 28 (11) 1456-1462.
• 37 Schilling AF, Priemel M, Timo FBeil. et al. Transgenic and knock out mice in skeletal research. Towards a molecular understanding of the mammalian skeleton. J Musculoskelet Neuronal Interact 2001; 01 (03) 275-289.
• 38 Sheng MH, Baylink DJ, Beamer WG. et al. Histomorphometric studies show that bone formation and bone mineral apposition rates are greater in C3H/HeJ (high-density) than C57BL/6J (low-density) mice during growth. Bone 1999; 25 (04) 421-429.
• 39 Sturmer EK, Seidlova-Wuttke D, Sehmisch S. et al. Standardized bending and breaking test for the normal and osteoporotic metaphyseal tibias of the rat: effect of estradiol, testosterone, and raloxifene. J Bone Miner Res 2006; 21 (01) 89-96.
• 40 Wehner T, Claes L, Niemeyer F. et al. Influence of the fixation stability on the healing time--a numerical study of a patient-specific fracture healing process. Clin Biomech (Bristol, Avon) 2010; 25 (06) 606-612.
• 41 Wehner T, Wolfram U, Henzler T. et al. Internal forces and moments in the femur of the rat during gait. J Biomech 2010; 43 (13) 2473-2479.
• 42 Wergedal JE, Sheng MH, Ackert-Bicknell CL. et al. Genetic variation in femur extrinsic strength in 29 different inbred strains of mice is dependent on variations in femur cross-sectional geometry and bone density. Bone 2005; 36 (01) 111-122.