Establishing Biomechanical Mechanisms in Mouse Models: Practical Guidelines for Systematically Evaluating Phenotypic Changes in the Diaphyses of Long Bones
dc.contributor.author | Jepsen, Karl J | en_US |
dc.contributor.author | Silva, Matthew J | en_US |
dc.contributor.author | Vashishth, Deepak | en_US |
dc.contributor.author | Guo, X Edward | en_US |
dc.contributor.author | van der Meulen, Marjolein CH | en_US |
dc.date.accessioned | 2015-06-01T18:52:02Z | |
dc.date.available | 2016-07-05T17:27:58Z | en |
dc.date.issued | 2015-06 | en_US |
dc.identifier.citation | Jepsen, Karl J; Silva, Matthew J; Vashishth, Deepak; Guo, X Edward; van der Meulen, Marjolein CH (2015). "Establishing Biomechanical Mechanisms in Mouse Models: Practical Guidelines for Systematically Evaluating Phenotypic Changes in the Diaphyses of Long Bones." Journal of Bone and Mineral Research 30(6): 951-966. | en_US |
dc.identifier.issn | 0884-0431 | en_US |
dc.identifier.issn | 1523-4681 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/111801 | |
dc.description.abstract | Mice are widely used in studies of skeletal biology, and assessment of their bones by mechanical testing is a critical step when evaluating the functional effects of an experimental perturbation. For example, a gene knockout may target a pathway important in bone formation and result in a “low bone mass” phenotype. But how well does the skeleton bear functional loads; eg, how much do bones deform during loading and how resistant are bones to fracture? By systematic evaluation of bone morphological, densitometric, and mechanical properties, investigators can establish the “biomechanical mechanisms” whereby an experimental perturbation alters whole‐bone mechanical function. The goal of this review is to clarify these biomechanical mechanisms and to make recommendations for systematically evaluating phenotypic changes in mouse bones, with a focus on long‐bone diaphyses and cortical bone. Further, minimum reportable standards for testing conditions and outcome variables are suggested that will improve the comparison of data across studies. Basic biomechanical principles are reviewed, followed by a description of the cross‐sectional morphological properties that best inform the net cellular effects of a given experimental perturbation and are most relevant to biomechanical function. Although morphology is critical, whole‐bone mechanical properties can only be determined accurately by a mechanical test. The functional importance of stiffness, maximum load, postyield displacement, and work‐to‐fracture are reviewed. Because bone and body size are often strongly related, strategies to adjust whole‐bone properties for body mass are detailed. Finally, a comprehensive framework is presented using real data, and several examples from the literature are reviewed to illustrate how to synthesize morphological, tissue‐level, and whole‐bone mechanical properties of mouse long bones. © 2015 American Society for Bone and Mineral Research | en_US |
dc.publisher | Academic Press | en_US |
dc.publisher | Wiley Periodicals, Inc. | en_US |
dc.subject.other | FUNCTION | en_US |
dc.subject.other | MOUSE MODELS | en_US |
dc.subject.other | BIOMECHANICAL MECHANISMS | en_US |
dc.subject.other | CORTICAL BONE | en_US |
dc.subject.other | BIOMECHANICS, BONE | en_US |
dc.title | Establishing Biomechanical Mechanisms in Mouse Models: Practical Guidelines for Systematically Evaluating Phenotypic Changes in the Diaphyses of Long Bones | en_US |
dc.type | Article | en_US |
dc.rights.robots | IndexNoFollow | en_US |
dc.subject.hlbsecondlevel | Internal Medicine and Specialities | en_US |
dc.subject.hlbtoplevel | Health Sciences | en_US |
dc.description.peerreviewed | Peer Reviewed | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/111801/1/jbmr2539.pdf | |
dc.identifier.doi | 10.1002/jbmr.2539 | en_US |
dc.identifier.source | Journal of Bone and Mineral Research | en_US |
dc.identifier.citedreference | Price CP, Herman BC, Lufkin T, Goldman HM, Jepsen KJ. Genetic variation in bone growth patterns defines adult mouse bone fragility. J Bone Miner Res. 2005; 20 ( 11 ): 1983 – 91. | en_US |
dc.identifier.citedreference | Voide R, van Lenthe GH, Muller R. Bone morphometry strongly predicts cortical bone stiffness and strength, but not toughness, in inbred mouse models of high and low bone mass. J Bone Miner Res. 2008; 23 ( 8 ): 1194 – 203. | en_US |
dc.identifier.citedreference | van Lenthe GH, Voide R, Boyd SK, Muller R. Tissue modulus calculated from beam theory is biased by bone size and geometry: implications for the use of three‐point bending tests to determine bone tissue modulus. Bone. 2008; 43 ( 4 ): 717 – 23. | en_US |
dc.identifier.citedreference | Yershov Y, Baldini TH, Villagomez S, et al. Bone strength and related traits in HcB/Dem recombinant congenic mice. J Bone Miner Res. 2001; 16 ( 6 ): 992 – 1003. | en_US |
dc.identifier.citedreference | Smith LM, Bigelow EM, Nolan BT, Faillace ME, Nadeau JH, Jepsen KJ. Genetic perturbations that impair functional trait interactions lead to reduced bone strength and increased fragility in mice. Bone. 2014; 67: 130 – 8. | en_US |
dc.identifier.citedreference | Selker F, Carter DR. Scaling of long bone fracture strength with animal mass. J Biomech. 1989; 22 ( 11–12 ): 1175 – 83. | en_US |
dc.identifier.citedreference | Mikic B, Van der Meulen MC, Kingsley DM, Carter DR. Mechanical and geometric changes in the growing femora of BMP‐5 deficient mice. Bone. 1996; 18 ( 6 ): 601 – 7. | en_US |
dc.identifier.citedreference | Macdonald HM, Cooper DM, McKay HA. Anterior‐posterior bending strength at the tibial shaft increases with physical activity in boys: evidence for non‐uniform geometric adaptation. Osteoporos Int. 2009; 20 ( 1 ): 61 – 70. | en_US |
dc.identifier.citedreference | Wagner DW, Lindsey DP, Beaupre GS. Deriving tissue density and elastic modulus from microCT bone scans. Bone. 2011; 49 ( 5 ): 931 – 8. | en_US |
dc.identifier.citedreference | Bi X, Patil CA, Lynch CC, et al. Raman and mechanical properties correlate at whole bone‐ and tissue‐levels in a genetic mouse model. J Biomech. 2011; 44 ( 2 ): 297 – 303. | en_US |
dc.identifier.citedreference | McBride SH, McKenzie JA, Bedrick BS, et al. Long bone structure and strength depend on BMP2 from osteoblasts and osteocytes, but not vascular endothelial cells. PLoS One. 2014; 9 ( 5 ): e96862. | en_US |
dc.identifier.citedreference | Amend SR, Uluckan O, Hurchla M, et al. Thrombospondin‐1 regulates bone homeostasis through effects on bone matrix integrity and nitric oxide signaling in osteoclasts. J Bone Miner Res. 2015; 30 ( 1 ): 106 – 15. | en_US |
dc.identifier.citedreference | Vashishth D. The role of the collagen matrix in skeletal fragility. Curr Osteoporos Rep. 2007; 5 ( 2 ): 62 – 6. | en_US |
dc.identifier.citedreference | Jepsen KJ, Akkus OJ, Majeska RJ, Nadeau JH. Hierarchical relationship between bone traits and mechanical properties in inbred mice. Mamm Genome. 2003; 14 ( 2 ): 97 – 104. | en_US |
dc.identifier.citedreference | Jepsen KJ, Bigelow EM, Schlecht SH. Women build long bones with less cortical mass relative to body size and bone size compared with men. Clin Orthop Relat Res. Forthcoming. Epub 2015 Feb 18. DOI: 10.1007/s11999‐015‐4184‐2. | en_US |
dc.identifier.citedreference | Miller LM, Little W, Schirmer A, Sheik F, Busa B, Judex S. Accretion of bone quantity and quality in the developing mouse skeleton. J Bone Miner Res. 2007; 22 ( 7 ): 1037 – 45. | en_US |
dc.identifier.citedreference | Main RP, Lynch ME, van der Meulen MC. Load‐induced changes in bone stiffness and cancellous and cortical bone mass following tibial compression diminish with age in female mice. J Exp Biol. 2014; 217 (Pt 10): 1775 – 83. | en_US |
dc.identifier.citedreference | Glatt V, Canalis E, Stadmeyer L, Bouxsein ML. Age‐related changes in trabecular architecture differ in female and male C57BL/6J mice. J Bone Miner Res. 2007; 22 ( 8 ): 1197 – 207. | en_US |
dc.identifier.citedreference | Ritchie RO, Koester KJ, Ionova S, Yao W, Lane NE, Ager JW 3rd. Measurement of the toughness of bone: a tutorial with special reference to small animal studies. Bone. 2008; 43 ( 5 ): 798 – 812. | en_US |
dc.identifier.citedreference | Wright S. Correlation and causation. J Agric Res. 1921; 20: 557 – 85. | en_US |
dc.identifier.citedreference | Waddington CH. Canalization of development and the inheritance of acquired characters. Nature. 1942; 14: 563 – 5. | en_US |
dc.identifier.citedreference | Currey JD. Mechanical properties of bone tissues with greatly differing functions. J Biomech. 1979; 12 ( 4 ): 313 – 9. | en_US |
dc.identifier.citedreference | Frost HM. Bone “mass” and the “mechanostat”: a proposal. Anat Rec. 1987; 219 ( 1 ): 1 – 9. | en_US |
dc.identifier.citedreference | Jepsen KJ, Hu B, Tommasini SM, et al. Phenotypic integration of skeletal traits during growth buffers genetic variants affecting the slenderness of femora in inbred mouse strains. Mamm Genome. 2009; 20 ( 1 ): 21 – 33. | en_US |
dc.identifier.citedreference | Beamer WG, Shultz KL, Churchill GA, et al. Quantitative trait loci for bone density in C57BL/6J and CAST/EiJ inbred mice. Mamm Genome. 1999; 10 ( 11 ): 1043 – 9. | en_US |
dc.identifier.citedreference | Li R, Tsaih S‐W, Shockley K, et al. Structural model analysis of multiple quantitative traits. PLoS Genet. 2006; 2 ( 7 ): 1046 – 57. | en_US |
dc.identifier.citedreference | Saless N, Litscher SJ, Houlihan MJ, et al. Comprehensive skeletal phenotyping and linkage mapping in an intercross of recombinant congenic mouse strains HcB‐8 and HcB‐23. Cells Tissues Organs. 2011; 194 ( 2–4 ): 244 – 8. | en_US |
dc.identifier.citedreference | Klein RF, Allard J, Avnur Z, et al. Regulation of bone mass in mice by the lipoxygenase gene Alox15. Science. 2004; 303 ( 5655 ): 229 – 32. | en_US |
dc.identifier.citedreference | Ducy P, Desbois C, Boyce B, et al. Increased bone formation in osteocalcin‐deficient mice. Nature. 1996; 382 ( 6590 ): 448 – 52. | en_US |
dc.identifier.citedreference | Maloul A, Rossmeier K, Mikic B, Pogue V, Battaglia T. Geometric and material contributions to whole bone structural behavior in GDF‐7‐deficient mice. Connect Tissue Res. 2006; 47 ( 3 ): 157 – 62. | en_US |
dc.identifier.citedreference | Yakar S, Canalis E, Sun H, et al. Serum IGF‐1 determines skeletal strength by regulating subperiosteal expansion and trait interactions. J Bone Miner Res. 2009; 24 ( 8 ): 1481 – 92. | en_US |
dc.identifier.citedreference | Saini V, Marengi DA, Barry KJ, et al. Parathyroid hormone (PTH)/PTH‐related peptide type 1 receptor (PPR) signaling in osteocytes regulates anabolic and catabolic skeletal responses to PTH. J Biol Chem. 2013; 288 ( 28 ): 20122 – 34. | en_US |
dc.identifier.citedreference | Brodt MD, Silva MJ. Aged mice have enhanced endocortical response and normal periosteal response compared with young‐adult mice following 1 week of axial tibial compression. J Bone Miner Res. 2010; 25 ( 9 ): 2006 – 15. | en_US |
dc.identifier.citedreference | Fritton JC, Myers ER, Wright TM, van der Meulen MC. Loading induces site‐specific increases in mineral content assessed by microcomputed tomography of the mouse tibia. Bone. 2005; 36 ( 6 ): 1030 – 8. | en_US |
dc.identifier.citedreference | Melville KM, Kelly NH, Surita G, et al. Effects of deletion of ER‐Alpha in osteoblast‐lineage cells on bone mass and adaptation to mechanical loading differs in female and male mice. J Bone Miner Res. Forthcoming. Epub 2015 Feb 24. DOI: 10.1002/jbmr.2488 | en_US |
dc.identifier.citedreference | Pelch KE, Carleton SM, Phillips CL, Nagel SC. Developmental exposure to xenoestrogens at low doses alters femur length and tensile strength in adult mice. Biol Reprod. 2012; 86 ( 3 ): 69. | en_US |
dc.identifier.citedreference | McCauley LK. Transgenic mouse models of metabolic bone disease. Curr Opin Rheumatol. 2001; 13 ( 4 ): 316 – 25. | en_US |
dc.identifier.citedreference | Murray SA. Mouse resources for craniofacial research. Genesis. 2011; 49 ( 4 ): 190 – 9. | en_US |
dc.identifier.citedreference | Menke DB. Engineering subtle targeted mutations into the mouse genome. Genesis. 2013; 51 ( 9 ): 605 – 18. | en_US |
dc.identifier.citedreference | Bouabe H, Okkenhaug K. Gene targeting in mice: a review. Methods Mol Biol. 2013; 1064: 315 – 36. | en_US |
dc.identifier.citedreference | Piret SE, Thakker RV. Mouse models: approaches to generating in vivo models for hereditary disorders of mineral and skeletal homeostasis. In: Thakker RV, Whyte MP, Eisen EJ, Igarashi T, editors. Genetics of bone biology and skeletal diseases. London, UK: Academic Press: 2013. p. 181 – 204. | en_US |
dc.identifier.citedreference | Blank RD. Breaking down bone strength: a perspective on the future of skeletal genetics. J Bone Miner Res. 2001; 16 ( 7 ): 1207 – 11. | en_US |
dc.identifier.citedreference | Bonadio J, Jepsen KJ, Mansoura MK, Jaenisch R, Kuhn JL, Goldstein SA. A murine skeletal adaptation that significantly increases cortical bone mechanical properties. Implications for human skeletal fragility. J Clin Invest. 1993; 92 ( 4 ): 1697 – 705. | en_US |
dc.identifier.citedreference | Brodt MD, Ellis CB, Silva MJ. Growing C57Bl/6 mice increase whole bone mechanical properties by increasing geometric and material properties. J Bone Miner Res. 1999; 14 ( 12 ): 2159 – 66. | en_US |
dc.identifier.citedreference | Jepsen KJ, Hu B, Tommasini SM, et al. Genetic randomization reveals functional relationships among morphologic and tissue‐quality traits that contribute to bone strength and fragility. Mamm Genome. 2007; 18 ( 6–7 ): 492 – 507. | en_US |
dc.identifier.citedreference | Turner CH, Burr DB. Basic biomechanical measurements of bone: a tutorial. Bone. 1993; 14 ( 4 ): 595 – 608. | en_US |
dc.identifier.citedreference | Burr DB, Milgrom C, Fyhrie D, et al. In vivo measurement of human tibial strains during vigorous activity. Bone. 1996; 18 ( 5 ): 405 – 10. | en_US |
dc.identifier.citedreference | Fritton SP, McLeod KJ, Rubin CT. Quantifying the strain history of bone: spatial uniformity and self‐similarity of low‐magnitude strains. J Biomech. 2000; 33 ( 3 ): 317 – 25. | en_US |
dc.identifier.citedreference | van der Meulen MC, Jepsen KJ, Mikic B. Understanding bone strength: size isn't everything. Bone. 2001; 29 ( 2 ): 101 – 4. | en_US |
dc.identifier.citedreference | Silva MJ, Brodt MD, Wopenka B, et al. Decreased collagen organization and content are associated with reduced strength of demineralized and intact bone in the SAMP6 mouse. J Bone Miner Res. 2006; 21 ( 1 ): 78 – 88. | en_US |
dc.identifier.citedreference | Burstein AH, Frankel VH. A standard test for laboratory animal bone. J Biomech. 1971; 4 ( 2 ): 155 – 8. | en_US |
dc.identifier.citedreference | Jepsen KJ, Pennington DE, Lee YL, Warman M, Nadeau J. Bone brittleness varies with genetic background in A/J and C57BL/6J inbred mice. J Bone Miner Res. 2001; 16 ( 10 ): 1854 – 62. | en_US |
dc.identifier.citedreference | Poundarik AA, Diab T, Sroga GE, et al. Dilatational band formation in bone. Proc Natl Acad Sci U S A. 2012; 109 ( 47 ): 19178 – 83. | en_US |
dc.identifier.citedreference | Carriero A, Zimmermann EA, Paluszny A, et al. How tough is brittle bone? Investigating osteogenesis imperfecta in mouse bone. J Bone Miner Res. 2014; 29 ( 6 ): 1392 – 401. | en_US |
dc.identifier.citedreference | Lynch JA, Silva MJ. In vivo static creep loading of the rat forelimb reduces ulnar structural properties at time‐zero and induces damage‐dependent woven bone formation. Bone. 2008; 42 ( 5 ): 942 – 9. | en_US |
dc.identifier.citedreference | Maruyama N, Shibata Y, Mochizuki A, et al. Bone micro‐fragility caused by the mimetic aging processes in alpha‐klotho deficient mice: in situ nanoindentation assessment of dilatational bands. Biomaterials. 2015; 47: 62 – 71. | en_US |
dc.identifier.citedreference | Vashishth D, Tanner KE, Bonfield W. Contribution, development and morphology of microcracking in cortical bone during crack propagation. J Biomech. 2000; 33 ( 9 ): 1169 – 74. | en_US |
dc.identifier.citedreference | Jepsen KJ, Goldstein SA, Kuhn JL, Schaffler MB, Bonadio J. Type‐I collagen mutation compromises the post‐yield behavior of Mov13 long bone. J Orthop Res. 1996; 14 ( 3 ): 493 – 9. | en_US |
dc.identifier.citedreference | Tang SY, Allen MR, Phipps R, Burr DB, Vashishth D. Changes in non‐enzymatic glycation and its association with altered mechanical properties following 1‐year treatment with risedronate or alendronate. Osteoporos Int. 2009; 20 ( 6 ): 887 – 94. | en_US |
dc.identifier.citedreference | Bouxsein ML, Boyd SK, Christiansen BA, Guldberg RE, Jepsen KJ, Muller R. Guidelines for assessment of bone microstructure in rodents using micro‐computed tomography. J Bone Miner Res. 2010 ‐25 ( 7 ): 1468 – 86. | en_US |
dc.identifier.citedreference | Dempster DW, Compston JE, Drezner MK, et al. Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res. 2013; 28 ( 1 ): 2 – 17. | en_US |
dc.identifier.citedreference | Patsch JM, Burghardt AJ, Yap SP, et al. Increased cortical porosity in type 2 diabetic postmenopausal women with fragility fractures. J Bone Miner Res. 2013; 28 ( 2 ): 313 – 24. | en_US |
dc.identifier.citedreference | You LD, Weinbaum S, Cowin SC, Schaffler MB. Ultrastructure of the osteocyte process and its pericellular matrix. Anat Rec A Discov Mol Cell Evol Biol. 2004; 278 ( 2 ): 505 – 13. | en_US |
dc.identifier.citedreference | Mader KS, Schneider P, Muller R, Stampanoni M. A quantitative framework for the 3D characterization of the osteocyte lacunar system. Bone. 2013; 57 ( 1 ): 142 – 54. | en_US |
dc.identifier.citedreference | Schneider P, Stauber M, Voide R, Stampanoni M, Donahue LR, Muller R. Ultrastructural properties in cortical bone vary greatly in two inbred strains of mice as assessed by synchrotron light based micro‐ and nano‐CT. J Bone Miner Res. 2007; 22 ( 10 ): 1557 – 70. | en_US |
dc.identifier.citedreference | Carriero A, Doube M, Vogt M, et al. Altered lacunar and vascular porosity in osteogenesis imperfecta mouse bone as revealed by synchrotron tomography contributes to bone fragility. Bone. 2014; 61: 116 – 24. | en_US |
dc.identifier.citedreference | Kuhnisch J, Seto J, Lange C, et al. Multiscale, converging defects of macro‐porosity, microstructure and matrix mineralization impact long bone fragility in NF1. PLoS One. 2014; 9 ( 1 ): e86115. | en_US |
dc.identifier.citedreference | Lai LP, Lotinun S, Bouxsein ML, Baron R, McMahon AP. Stk11 (Lkb1) deletion in the osteoblast lineage leads to high bone turnover, increased trabecular bone density and cortical porosity. Bone. 2014; 69: 98 – 108. | en_US |
dc.identifier.citedreference | Silva MJ, Brodt MD, Fan Z, Rho JY. Nanoindentation and whole‐bone bending estimates of material properties in bones from the senescence accelerated mouse SA MP6. J Biomech. 2004; 37 ( 11 ): 1639 – 46. | en_US |
dc.identifier.citedreference | Schriefer JL, Robling AG, Warden SJ, Fournier AJ, Mason JJ, Turner CH. A comparison of mechanical properties derived from multiple skeletal sites in mice. J Biomech. 2005; 38 ( 3 ): 467 – 75. | en_US |
dc.owningcollname | Interdisciplinary and Peer-Reviewed |
Files in this item
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.