Variation in within-bone stiffness measured by nanoindentation in mice bred for high levels of voluntary wheel running

Journal of Anatomy

Volumn 216, Issue 1, 2010, Pages 121-131

  Middleton, Kevin M ^a,c   Goldstein, Beth D ^b   Guduru, Pradeep R ^b   Waters, Julie F ^b   Kelly, Scott A ^c   Swartz, Sharon M ^a,b   Garland Jr, T ^c  

^a BROWN UNIVERSITY   (United States)

^b Brown University   (United States)

^c UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Artificial selection; Bone; Exercise; Experimental evolution; Material properties; Nanoindentation

Indexed keywords

ENDOCANNABINOID; LEPTIN;

ANATOMICAL VARIATION; ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; ARTIFICIAL SELECTION; BODY MASS; BONE STRUCTURE; COMPUTER ASSISTED TOMOGRAPHY; CONTROLLED STUDY; DIAPHYSIS; FEMALE; GASTROCNEMIUS MUSCLE; MORPHOMETRICS; MOUSE; NONHUMAN; PHENOTYPE; PHYSICAL ACTIVITY; PRIORITY JOURNAL; PROTEIN BLOOD LEVEL; RIGIDITY; YOUNG MODULUS;

ADAPTATION, PHYSIOLOGICAL; ANIMALS; BODY MASS INDEX; BONE AND BONES; BREEDING; COMPRESSIVE STRENGTH; EVOLUTION; FEMALE; MICE; MICE, INBRED ICR; MODELS, ANIMAL; MOTOR ACTIVITY; REPRODUCIBILITY OF RESULTS; SELECTION, GENETIC; X-RAY MICROTOMOGRAPHY;

MAMMALIA; MUS;

EID: 73149100558     PISSN: 00218782     EISSN: 14697580     Source Type: Journal    
DOI: 10.1111/j.1469-7580.2009.01175.x     Document Type: Article

References (129)

1. Akhter MP, Fan Z, Rho JY. Bone intrinsic material properties in three inbred mouse strains. Calcif Tissue Int 2004, 75:416-420.
2. Amanat N, He LH, Swain MV. The effect of zoledronic acid on the intrinsic material properties of healing bone: an indentation study. Med Eng Physics 2008, 30:843-847.
3. Bab IA. Regulation of skeletal remodeling by the endocannabinoid system. Ann N Y Acad Sci 2007, 1116:414-422.
4. Bab IA, Zimmer A. Cannabinoid receptors and the regulation of bone mass. Br J Pharmacol 2008, 153:182-188.
5. Babij P, Zhao W, Small C. High bone mass in mice expressing a mutant LRP5 gene. J Bone Miner Res 2003, 18:960-974.
6. Beamer WG, Shultz KL, Ackert-Bicknell CL. Genetic dissection of mouse distal chromosome 1 reveals three linked BMD QTLs with sex-dependent regulation of bone phenotypes. J Bone Miner Res 2007, 22:1187-1196.
7. Bennett AF. Experimental evolution and the Krogh Principle: generating biological novelty for functional and genetic analyses. Physiol Biochem Zool 2003, 76:1-11.
8. Biewener AA. Locomotory stresses in the limb bones of two small mammals: the ground squirrel and chipmunk. J Exp Biol 1983, 103:131-154.
9. Biewener AA, Thomason J, Lanyon LE. Mechanics of locomotion and jumping in the forelimb of the horse (Equus): in vivo stress developed in the radius and metacarpus. J Zool Lond 1983, 201:67-82.
10. Biewener AA, Swartz SM, Bertram JEA. Bone modeling during growth: dynamic strain equilibrium in the chick tibiotarsus. Calcif Tissue Int 1986, 39:390-395.
11. Bigley RF, Gibeling JC, Stover SM. Volume effects on fatigue life of equine cortical bone. J Biomech 2007, 40:3548-3554.
12. Bower AL, Lang DH, Vogler GP. QTL analysis of trabecular bone in BXD F2 and RI mice. J Bone Miner Res 2006, 21:1267-1275.
13. Broz JJ, Simske SJ, Greenberg AR. Effects of rehydration state on the flexural properties of whole mouse long bones. J Biomech Eng 1993, 115:447-449.
14. Carlson KJ, Judex S. Increased non-linear locomotion alters diaphyseal bone shape. J Exp Biol 2007, 210:3117-3125.
15. Carter DR. The relationship between in vivo strains and cortical bone remodeling. Crit Rev Biomed Eng 1982, 8:1-28.
16. Carter DR, Fyhrie DP, Whalen RT. Trabecular bone density and loading history: regulation of connective tissue biology by mechanical energy. J Biomech 1987, 20:785-794.
17. Carter PA, Swallow JG, Davis SJ. Nesting behavior of house mice (Mus domesticus) selected for increased wheel-running activity. Behav Genet 2000, 30:85-94.
18. Cornish J, Callon KE, Bava U. Leptin directly regulates bone cell function in vitro and reduces bone fragility in vivo. J Endocrinol 2002, 175:405-415.
19. Curran-Everett D. Multiple comparison: philosophies and illustrations. Am J Physiol Reg Integr Comp Physiol 2000, 279:r1-r8.
20. Curran-Everett D, Benos DJ. Guidelines for reporting statistics in journals published by the American Physiological Society. J Appl Physiol 2004, 97:457-459.
21. Currey JD. The many adaptations of bone. J Biomech 2003, 36:1487-1495.
22. De Souza RL, Matsuura M, Eckstein F. Non-invasive axial loading of mouse tibiae increases cortical bone formation and modifies trabecular organization: a new model to study cortical and cancellous compartments in a single loaded element. Bone 2005, 37:810-818.
23. Ducy P, Amling M, Takeda S. Leptin inhibits bone formation through a hypothalamic relay: a central control on bone mass. Cell 2000, 100:197-207.
24. Dumke CL, Rhodes JS, Garland T. Genetic selection of mice for high voluntary wheel running: effect on skeletal muscle glucose uptake. J Appl Physiol 2001, 91:1289-1297.
25. Eisen EJ. Selection for components related to body composition in mice: direct responses. Theor Appl Genet 1987, 74:793-801.
26. Eisen EJ. Restricted index selection in mice designed to change body fat without changing body weight: direct responses. Theor Appl Genet 1992, 83:973-980.
27. Eisen EJ, Benyon LS, Douglas JA. Long-term restricted index selection in mice designed to change fat content without changing body size. Theor Appl Genet 1995, 91:340-345.
28. Evans FG, Lebow M. Regional difference in some of the physical properties of the human femur. J Appl Physiol 1951, 3:563-572.
29. Fan Z, Swadener JG, Rho JY. Anisotropic properties of human tibial cortical bone as measured by nanoindentation. J Orthop Res 2002, 20:806-810.
30. Fan Z, Smith PA, Harris GF. Comparison of nanoindentation measurements between osteogenesis imperfecta Type III and Type IV and between different anatomic locations (femur/tibia versus iliac crest). Conn Tiss Res 2007, 48:70-75.
31. Fischer MS, Schilling N, Schmidt M. Basic limb kinematics of small therian mammals. J Exp Biol 2002, 205:1315-1338.
32. Frost HM. Skeletal structural adaptations to mechanical usage (SATMU): 4. Mechanical influences on intact fibrous tissues. Anat Rec 1990, 226:433-439.
33. Frost HM. Bone's mechanostat: a 2003 update. Anat Rec A 2003, 275:1081-1101.
34. Gammie SC, Hasen NS, Rhodes JS. Predatory aggression, but not maternal or intermale aggression, is associated with high voluntary wheel-running behavior. Horm Behav 2003, 44:209-221.
35. Garland T, Bels VL, Gasc J-P, Casinos A. Selection experiments: an under-utilized tool in biomechanics and organismal biology. Vertebrate Biomechanics and Evolution 2003, 23-56. In, eds, pp, Oxford, BIOS Scientific Publishers, Ltd
36. Garland T, Freeman PW. Selective breeding for high endurance running increases hindlimb symmetry. Evolution 2005, 59:1851-1854.
37. Garland T, Kelly SA. Phenotypic plasticity and experimental evolution. J Exp Biol 2006, 209:2344-2361.
38. Garland T, Morgan MT, Swallow JG. Evolution of a small-muscle polymorphism in line of house mice selected for high activity levels. Evolution 2002, 56:1267-1275.
39. Girard I, Garland T. Plasma corticosterone response to acute and chronic voluntary exercise in female house mice. J Appl Physiol 2002, 92:1553-1561.
40. Girard IA, Rezende EL, Garland T. Leptin levels and body composition of mice selectively bred for high voluntary locomotor activity. Physiol Biochem Zool 2007, 80:568-579.
41. Guderley H, Houle-Leroy P, Diffee GM. Morphometry, ultrastructure, myosin isoforms, and metabolic capacities of the 'mini muscles' favoured by selection for high activity in house mice. Comp Biochem Physiol B 2006, 144:271-282.
42. Guderley H, Joanisse DR, Mokas S. Altered fibre types in gastrocnemius muscle of high wheel-running selected mice with mini-muscle phenotypes. Comp Biochem Physiol B 2008, 149:490-500.
43. Hamrick MW, McPherron AC, Lovejoy CO. Femoral morphology and cross-sectional geometry of adult myostatin-deficient mice. Bone 2000, 27:343-349.
44. Hamrick MW, Samaddar T, Pennington C. Increased muscle mass with myostatin deficiency improves gains in bone strength with exercise. J Bone Miner Res 2006, 21:477-483.
45. Hannon RM, Kelly SA, Middleton KM. Phenotypic effects of the 'mini-muscle' allele in a large HR x C57BL/6J mouse backcross. J Hered 2008, 99:349-354.
46. Hartmann J, Garland T, Hannon RM. Fine mapping of 'mini-muscle', a recessive mutation causing reduced hind-limb muscle mass in mice. J Hered 2008, 99:679-687.
47. Hengsberger S, Kulik A, Zysset PK. Nanoindentation discriminates the elastic properties of individual human bone lamellae under dry and physiological conditions. Bone 2002, 30:178-184.
48. Houle-Leroy P, Guderley H, Swallow JG. Artificial selection for high activity favors mighty mini-muscle in house mice. Am J Physiol Reg Integr Comp Physiol 2003, 284:R433-R443.
49. Huiskes R, Ruimerman R, van Lenthe GH. Effects of mechanical forces on maintenance and adaptation of form in trabecular bone. Nature 2000, 405:704-706.
50. Idris AI, van't Hof RJ, Greig IR. Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors. Nat Med 2005, 11:774-779.
51. Idris AI, Sophocleous A, Landao-Bassonga E. Cannabinoid receptor type 1 protects against age-related osteoporosis by regulating osteoblast and adipocyte differentiation in marrow stromal cells. Cell Metab 2009, 10:139-147.
52. Jang BK, Matsubara H. Influence of porosity on hardness and Young's modulus of nanoporous EB-PVD TBCs by nanoindentation. Mater Lett 2005, 59:3462-3466.
53. Ji B, Gao H. Mechanical properties of nanostructure of biological materials. J Mech Phys Solids 2004, 52:1963-1990.
54. Jiao Y, Chiu H, Fan Z. Quantitative trait loci that determine mouse tibial nanoindentation properties in an F2 population derived from C57BL/6J X C3H/Hej. Calcif Tissue Int 2007, 80:383-390.
55. Karsenty G. Convergence between bone and energy homeostases: leptin regulation of bone mass. Cell Metab 2006, 4:341-348.
56. Kavukcuoglu NB, Denhardt DT, Guzelsu N. Osteopontin deficiency and aging on nanomechanics of mouse bone. J Biomed Mater Res A 2007, 83:136-144.
57. Keeney BK, Raichlen DA, Meek TH. Differential response to a selective cannabinoid receptor antagonist (SR141716: Rimonabant) in female mice from lines selectively bred for high voluntary wheel-running behaviour. Behav Pharmacol 2008, 19:812-820.
58. Kelly SA, Czech PP, Wight JT. Experimental evolution and phenotypic plasticity of hindlimb bones in high-activity house mice. J Morph 2006, 267:360-374.
59. Kesavan C, Mohan S, Oberholtzer S. Mechanical loading-induced gene expression and BMD changes are different in two inbred mouse strains. J Appl Physiol 2005, 99:1951-1957.
60. Kesavan C, Mohan S, Srivastava AK. Identification of genetic loci that regulate bone adaptive response to mechanical loading in C57BL/6J and C3H/Hej mice intercross. Bone 2006, 39:634-643.
61. Kesavan C, Baylink DJ, Kapoor S. Novel loci regulating bone anabolic response to loading: expression QTL analysis in C57BL/6J x C3H/Hej mice cross. Bone 2007, 41:223-230.
62. Kodama Y, Umemura Y, Nagasawa S. Exercise and mechanical loading increase periosteal bone formation and whole bone strength in C57BL/6J but not in C3H/Hej mice. Calcif Tissue Int 2000, 66:298-306.
63. Koller DL, Schreifer J, Sun Q. Genetic effects for femoral biomechanics, structure, and density in C57BL/6J and C3H/Hej inbred mouse strains. J Bone Miner Res 2003, 18:1758-1765.
64. Lakes R. Materials with structural hierarchy. Nature 1993, 361:511-515.
65. Lang DH, Sharkey NA, Mack HA. Quantitative trait loci analysis of structural and material skeletal phenotypes in C57BL/6J and DBA/2 second-generation and recombinant inbred mice. J Bone Miner Res 2005, 20:88-99.
66. Lanyon LE. Osteocytes, strain detection, bone modeling and remodeling. Calcif Tissue Int 1993, 53:S102-S106.
67. Lanyon LE, Goodship AE, Pye CJ. Mechanically adaptive bone remodelling. J Biomech 1982, 15:141-154.
68. Lee KCL, Maxwell A, Lanyon LE. Validation of a technique for studying functional adaptation of the mouse ulna in response to mechanical loading. Bone 2002, 31:1-9.
69. Leong PL, Morgan EF. Measurement of fracture callus material properties via nanoindentation. Acta Biomat 2008, 4:1569-1575.
70. Lessels CM, Boag PT. Unrepeatable repeatabilities: a common mistake. Auk 1987, 104:116-121.
71. MacDonald BT, Joiner DM, Oyserman SM. Bone mass is inversely proportional to Dkk1 levels in mice. Bone 2007, 41:331-339.
72. Malisch JL, Saltzman W, Gomes FR. Baseline and stress-induced plasma corticosterone concentrations of mice selectively bred for high voluntary wheel running. Physiol Biochem Zool 2007, 80:146-156.
73. Malisch JL, Breuner C, Gomes FR. Circadian pattern of total and free corticosterone concentrations, corticosteroid-binding globulin, and physical activity in mice selectively bred for high voluntary wheel-running behavior. Gen Comp Endocrinol 2008, 156:210-217.
74. Malisch JL, Breuner CW, Kolb EM. Behavioral despair and home-cage activity in mice with chronically elevated baseline corticosterone concentrations. Behav Genet 2009, 39:192-209.
75. Martin RB. Toward a unifying theory of bone remodeling. Bone 2000, 26:1-6.
76. Martin RB. The importance of mechanical loading in bone biology and medicine. J Musculoskelet Neuronal Interact 2007, 7:48-53.
77. van der Meulen MCH, Huiskes R. Why mechanobiology? A survey article. J Biomech 2002, 35:401-414.
78. van der Meulen MCH, Beaupré GS, Carter DR. Mechanobiologic influences in long bone cross-sectional growth. Bone 1993, 14:635-642.
79. Middleton KM, Kelly SA, Garland T. Selective breeding as a tool to probe skeletal response to high voluntary locomotor activity in mice. Integr Comp Bio 2008a, 48:394-410.
80. Middleton KM, Shubin CE, Moore DC. The relative importance of genetics and phenotypic plasticity in dictating bone morphology and mechanics in aged mice: evidence from an artificial selection experiment. Zoology 2008b, 111:135-147.
81. Mosley JR, March BM, Lynch J. Strain magnitude related changes in whole bone architecture in growing rats. Bone 1997, 20:191-198.
82. Nazarian A, von Stechow D, Zurakowski D. Bone volume fraction explains the variation in strength and stiffness of cancellous bone affected by metastatic cancer and osteoporosis. Calcif Tissue Int 2008, 83:368-379.
83. Ofek O, Karsak M, Leclerc N. Peripheral cannabinoid receptor, CB2, regulates bone mass. Proc Natl Acad Sci U S A 2006, 103:696-701.
84. Oliver WC, Pharr GM. An improved technique for determining hardness and elastic modulus using load and displacement-sensing indentation systems. J Mater Res 1992, 7:1564-1583.
85. Parfitt AM. What is the normal rate for bone remodeling? Bone 2004, 35:1-3.
86. R: A Language and Environment for Statistical Computing 2008, http://www.R-project.org, R Foundation for Statistical Computing; Vienna. Available at:
87. Radovic M, Lara-Curzio E, Riester L. Comparison of different experimental techniques for determination of elastic properties of solids. Mater Sci Eng A 2004, 368:56-70.
88. Ralston SH, Galwey N, MacKay I. Loci for regulation of bone mineral density in men and women identified by genome wide linkage scan: the FAMOS study. Hum Mol Genet 2005, 14:943-951.
89. Ramasamy JG, Akkus O. Local variations in the micromechanical properties of mouse femur: the involvement of collagen fiber orientation and mineralization. J Biomech 2007, 40:910-918.
90. Rezende EL, Garland T, Chappell MA. Maximum aerobic performance in lines of Mus selected for high wheel-running activity: effects of selection, oxygen availability and the mini-muscle phenotype. J Exp Biol 2006a, 209:115-127.
91. Rezende EL, Kelly SA, Gomes FR. Effects of size, sex, and voluntary running speeds on costs of locomotion in lines of laboratory mice selectively bred for high wheel-running activity. Physiol Biochem Zool 2006b, 79:83-99.
92. Rho JY, Pharr GM. Effects of drying on the mechanical properties of bovine femur measured by nanoindentation. J Mater Sci Mater Med 1999, 10:485-488.
93. Rho JY, Tsui TY, Pharr GM. Elastic properties of human cortical and trabecular lamellar bone measured by nanoindentation. Biomaterials 1997, 18:1325-1330.
94. Rho JY, Roy ME, Tsui TY. Elastic properties of microstructural components of human bone tissue as measured by nanoindentation. J Biomed Mat Res 1999a, 45:48-54.
95. Rho JY, Zioupos P, Currey JD. Variations in the individual thick lamellar properties within osteons by nanoindentation. Bone 1999b, 25:295-300.
96. Rho JY, Zioupos P, Currey JD. Microstructural elasticity and regional heterogeneity in human femoral bone of various ages examined by nano-indentation. J Biomech 2002, 35:189-198.
97. Rhodes JS, Gammie SC, Garland T. Neurobiology of mice selected for high voluntary wheel-running activity. Integr Comp Bio 2005, 45:438-455.
98. Robling AG, Turner CH. Mechanotransduction in bone: genetic effects on mechanosensitivity in mice. Bone 2002, 31:562-569.
99. Robling AG, Li J, Shultz KL. Evidence for a skeletal mechanosensitivity gene on mouse chromosome 4. FASEB J 2003, 17:324-326.
100. Robling AG, Warden SJ, Shultz KL. Genetic effects on bone mechanotransduction in congenic mice harboring bone size and strength quantitative trait loci. J Bone Miner Res 2007, 22:984-991.
101. Rossi F, Siniscalco D, Luongo L. The endovanilloid/endocannabinoid system in human osteoclasts: possible involvement in bone formation and resorption. Bone 2009, 44:476-484.
102. Roy ME, Rho JY, Tsui TY. Mechanical and morphological variation of the human lumbar vertebral cortical and trabecular bone. J Biomed Mat Res 1999, 44:191-197.
103. Rubin CT. Skeletal strain and the functional significance of bone architecture. Calcif Tissue Int 1984, 36:S11-S18.
104. Rubin CT, Lanyon LE. Limb mechanics as a function of speed and gait: a study of functional strains in the radius and tibia of horse and dog. J Exp Biol 1982, 101:187-211.
105. Rubin CT, Lanyon LE. Regulation of bone mass by mechanical strain magnitude. Calcif Tissue Int 1985, 37:411-417.
106. Rüegsegger P, Cowin SC. Imaging of bone structure. Bone Mechanics Handbook 2001, 9-1-9-24. In, ed, pp, Boca Raton, FL, CRC Press
107. Ryan SD, Williams JL. Tensile testing of rodlike trabeculae excised from bovine femoral bone. J Biomech 1989, 22:351-355.
108. Silva MJ, Brodt MD, Fan Z. Nanoindentation and whole-bone bending estimates of material properties in bones from the senescence accelerated mouse SAMP6. J Biomech 2004, 37:1639-1646.
109. Skedros JG, Hunt KJ. Does the degree of laminarity correlate with site-specific differences in collagen fibre orientation in primary bone? An evaluation in the turkey ulna diaphysis. J Anat 2004, 205:121-134.
110. Skedros JG, Mendenhall SD, Kiser CJ. Interpreting cortical bone adaptation and load history by quantifying osteon morphotypes in circularly polarized light images. Bone 2009, 44:392-403.
111. Steppan CM, Crawford DT, Chidsey-Frink KL. Leptin is a potent stimulator of bone growth in ob/ob mice. Regul Pept 2000, 92:73-78.
112. Storey JD. A direct approach to false discovery rates. J R Stat Soc Series B Stat Methodol 2002, 64:479-498.
113. Swallow JG, Carter PA, Garland T. Artificial selection for increased wheel-running behavior in house mice. Behav Genet 1998, 28:227-237.
114. Swallow JG, Koteja P, Carter PA. Artificial selection for increased wheel-running activity in house mice results in decreased body mass at maturity. J Exp Biol 1999, 202:2513-2520.
115. Swallow JG, Hayes JP, Koteja P, Garland T, Rose MR. Selection experiments and experimental evolution of performance and physiology. Experimental Evolution: Concepts, Methods, and Applications of Selection Experiments 2009, 301-351. In, eds, pp, Berkeley, University of California Press
116. Syme DA, Evashuk K, Grintuch B. Contractile abilities of normal and 'mini' triceps surae muscle from mice (Mus domesticus) selectively bred for high voluntary wheel running. J Appl Physiol 2005, 99:1308-1316.
117. Tai K, Dao M, Suresh S. Nanoscale heterogeneity promotes energy dissipation in bone. Nat Mater 2007, 6:454-462.
118. Tam J, Ofek O, Fride E. Involvement of neuronal cannabinoid receptor CB1 in regulation of bone mass and bone remodeling. Mol Pharmacol 2006, 70:786-792.
119. Tam J, Trembovler V, Di Marzo V. The cannabinoid CB1 receptor regulates bone formation by modulating adrenergic signaling. FASEB J 2008, 22:285-294.
120. Taylor C, Schmidt-Nielsen K, Raab J. Scaling of the energetic cost of running to body size in mammals. Am J Physiol 1970, 219:1104-1107.
121. Taylor D. Fatigue of bone and bones: an analysis based on stressed volume. J Orthop Res 1998, 16:163-169.
122. Taylor D. Scaling effects in the fatigue strength of bones from different animals. J Theor Biol 2000, 206:299-306.
123. Taylor D, Kuiper JH. The prediction of stress fractures using a 'stressed volume' concept. J Orthop Res 2001, 19:919-926.
124. Taylor D, O'Brien FJ, Prina-Mello A. Compression data on bovine bone confirms that a 'stressed volume' principle explains the variability of fatigue strength results. J Biomech 1999, 32:1199-1203.
125. Turner CH, Rho JY, Takano Y. The elastic properties of trabecular and cortical bone tissues are similar: results from two microscopic measurement techniques. J Biomech 1999, 32:437-441.
126. Vaanholt LM, Meerlo P, Garland T. Plasma adiponectin is increased in mice selectively bred for high wheel-running activity, but not by wheel running per se. Horm Metab Res 2007, 39:377-383.
127. Vaanholt LM, Jonas I, Doornbos M. Metabolic and behavioral responses to high-fat feeding in mice selectively bred for high wheel-running activity. Int J Obes 2008, 32:1566-1575.
128. Witte H, Biltzinger J, Hackert R. Torque patterns of the limbs of small therian mammals during locomotion on flat ground. J Exp Biol 2002, 205:1339-1353.
129. Zysset PK, Guo XE, Hoffler CE. Elastic modulus and hardness of cortical and trabecular bone lamellae measured by nanoindentation in the human femur. J Biomech 1999, 32:1005-1012.