Investigating the Inbred Strain-Specific Response to Biglycan-Deficiency and Exercise: A Study in Genetically-Mediated Skeletal Adaptation

Bone is an exquisitely evolved connective tissue that serves structural and metabolic roles in the body. Bone fragility leading to fracture is a significant medical and economic burden facing our society. Each year, 1.5 million Americans suffer an agerelated fracture, resulting in direct-care expenditures of 18 billion dollars a year and often leading to decreased quality of life or even death.

Animals with targeted mutations in a bone matrix protein (KO) are utilized to study the protein’s roles in regulating extracellular matrix (ECM) deposition and architecture and understanding how these functions relate to bone disease and fracture etiology.

The importance of skeletal loading for the maintenance/increase of bone mass was suggested as early as 1892. In addition to increased size, mechanical loading influences bone ECM quality. Since many diseases influence the mechanical integrity of bone through altered tissue quality, mechanical stimulation may be a practical way to prevent/treat ECM deficiencies.

Mouse inbred strain-specific responses in bone have been demonstrated following mechanical stimulation and bone regeneration. No study has demonstrated that the response to a genetic deletion can exhibit inbred-strain-specific characteristics, or that phenotypic changes can be modulated with mechanical stimulation. It was hypothesized that the response to a genetic deletion (the bone matrix protein biglycan, bgn), mechanical stimulation (running) and a combination of these two variables would display inbred-strain-specific characteristics in the tibiae of C57BL6/129 (B6;129) and C3H/He (C3H) male mice.

This dissertation establishes for the first time that an inbred strain-specific response to genetic deletion exists, further develops the roles that biglycan plays in regulating collagen and mineral in vivo and links these in vivo roles with mechanical integrity. Without addition of new bone, exercise altered the pre-existing ECM which influenced tissue quality and mechanical integrity. In B6;129 KO, exercise-induced changes in tissue composition compensated for tissue-level mechanical deficiencies, suggesting that mechanical stimulation may be effective as a therapeutic intervention for diseases associated with deficiencies in bone quality. These studies provide new insights into inbred strain research which has important implications to the proper interpretation of investigations into the effects of genetic deficiencies and loading on the skeleton.

Year	Entry
2002	Wang X, Li X, Bank RA, Agrawal CM. Effects of collagen unwinding and cleavage on the mechanical integrity of the collagen network in bone. Calcif Tiss Int. August 2002;71(2):186-192.
2004	Ward K, Alsop C, Caulton J, Rubin C, Adams J, Mughal Z. Low magnitude mechanical loading is osteogenic in children with disabling conditions. J Bone Miner Res. March 2004;19(3):360-369.
1999	Timlin JA, Carden A, Morris MD. Chemical microstructure of cortical bone probed by Raman transects. Appl Spectrosc. November 1999;53(11):1429-1435.
1993	Biewener AA. Safety factors in bone strength. Calcif Tiss Int. February 1993;53(suppl 1):S68-S74.
2000	Timlin JA, Carden A, Morris MD, Rajachar RM, Kohn DH. Raman spectroscopic imaging markers for fatigue-related microdamage in bovine bone. Anal Chem. May 15, 2000;72(10):2229-2236.
2004	Somerville JM, Aspden RM, Armour KE, Armour KJ, Reid DM. Growth of C57Bl/6 mice and the material and mechanical properties of cortical bone from the tibia. Calcif Tiss Int. May 2004;74(5):469-475.
1999	Boskey AL, Wright TM, Blank RD. Collagen and bone strength. J Bone Miner Res. March 1999;14(3):330-335.
1995	Landis WJ. The strength of a calcified tissue depends in part on the molecular structure and organization of its constituent mineral crystals in their organic matrix. Bone. May 1995;16(5):533-544.
2004	Rubin C, Recker R, Cullen D, Ryaby J, McCabe J, McLeod K. Prevention of postmenopausal bone loss by a low‐magnitude, high‐frequency mechanical stimuli: a clinical trial assessing compliance, efficacy, and safety. J Bone Miner Res. March 2004;19(3):343-351.
1997	Umemura Y, Ishiko T, Yamauchi T, Kurono M, Mashiko S. Five jumps per day increase bone mass and breaking force in rats. J Bone Miner Res. September 1997;12(10):1480-1485.
2002	Wachter NJ, Krischak GD, Mentzel M, Sarkar MR, Ebinger T, Kinz L, Claes L, Augat P. Correlation of bone mineral density with strength and microstructural parameters of cortical bone in vitro. Bone. July 2002;31(1):90-95.
2001	Turner CH, Hsieh Y, Müller R, Bouxsein ML, Rosen CJ, McCrann ME, Donahue LR, Beamer WG. Variation in bone biomechanical properties, microstructure, and density in BXH recombinant inbred mice. J Bone Miner Res. February 2001;16(2):206-213.
2001	NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. February 14, 2001;285(6):785-795.
2000	Heaney RP, Abrams S, Dawson-Hughes B, Looker A, Marcus R, Matkovic V, Weaver C. Peak bone mass. Osteoporos Int. December 2000;11(12):985-1009.
1998	Akhter MP, Cullen DM, Pedersen EA, Kimmel DB, Recker RR. Bone response to in vivo mechanical loading in two breeds of mice. Calcif Tiss Int. November 1998;63(5):442-449.
1994	Roach HI. Why does bone matrix contain non‐collagenous proteins? the possible roles of osteocalcin, osteonectin, osteopontin and bone sialoprotein in bone mineralisation and resorption. Cell Biol Int. 1994;18(6):617-628.
2000	Turner CH, Hsieh Y, Müller R, Bouxsein ML, Baylink DJ, Rosen CJ, Grynpas MD, Donahue LR, Beamer WG. Genetic regulation of cortical and trabecular bone strength and microstructure in inbred strains of mice. J Bone Miner Res. June 2000;15(6):1126-1131.
2003	Amblard D, Lafage-Proust M-H, Laib A, Thomas T, Rüegsegger P, Alexandre C, Vico L. 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. March 2003;18(3):561-569.
1989	Jones BH, Harris JM, Vinh TN, Rubin C. Exercise-induced stress fractures and stress reactions of bone: epidemiology, etiology, and classification. Exerc Sport Sci Rev. January 1989;17(1):379-422.
1990	Kuhn JL, Goldstein SA, Feldkamp LA, Goulet RW, Jesion G. Evaluation of a microcomputed tomography system to study trabecular bone structure. J Orthop Res. 1990;8(6):833-842.
2005	Nyman JS, Reyes M, Wang X. Effect of ultrastructural changes on the toughness of bone. Micron. October–December 2005;36(7-8):566-582.
2004	Akkus O, Adar F, Schaffler MB. Age-related changes in physicochemical properties of mineral crystals are related to impaired mechanical function of cortical bone. Bone. March 2004;34(4):443-453.
1996	Carter DR, Van der Meulen MCH, Beaupré GS. Mechanical factors in bone growth and development. Bone. January 1996;18(1)(suppl 1):S5-S10.
1998	Weiner S, Wagner HD. The material bone: structure-mechanical function relations. Ann Rev Mater Sci. August 1998;28:271-298.
1996	Gustafson MB, Martin RB, Gibson V, Storms DH, Stover SM, Gibeling J, Griffin L. Calcium buffering is required to maintain bone stiffness in saline solution. J Biomech. September 1996;29(9):1191-1194.
1999	Burger EH, Klein-Nulend J. Mechanotransduction in bone: role of the lacunocanalicular network. FASEB J. May 1999;12(9001):S101-S112.
2001	Rubin C, Turner AS, Bain S, Mallinckrodt C, McLeod K. Low mechanical signals strengthen long bones. Nature. August 9, 2001;412(6847):603-604.
1992	Weiner S, Traub W. Bone structure: from ȧngstroms to microns. FASEB J. February 1992;6(3):879-885.
1999	Adami S, Gatti D, Braga V, Bianchini D, Rossini M. Site-specific effects of strength training on bone structure and geometry of ultradistal radius in postmenopausal women. J Bone Miner Res. January 1999;14(1):120-124.
2005	De Souza RL, Matsuura M, Eckstein F, Rawlinson SCF, Lanyon LE, Pitsillides AA. 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. December 2005;37(6):810-818.
1996	Beamer WG, Donahue LR, Rosen CJ, Baylink DJ. Genetic variability in adult bone density among inbred strains of mice. Bone. May 1996;18(5):397-403.
2002	Wang X, Shen X, Li X, Agrawal CM. Age-related changes in the collagen network and toughness of bone [published correction appears in Bone. 2003;32(1):107]. Bone. 2002;31(1):1-7.
2001	Wang X, Bank RA, Tekoppele JM, Agrawal CM. The role of collagen in determining bone mechanical properties. J Orthop Res. 2001;19(6):1021-1026.
2001	Jepsen KJ, Pennington DE, Lee Y, Warman M, Nadeau J. Bone brittleness varies with genetic background in A/J and C57BL/6J inbred mice. J Bone Miner Res. October 2001;16(10):1854-1862.
1991	Fratzl P, Fratzl-Zelman N, Klaushofer K, Vogl G, Koller K. Nucleation and growth of mineral crystals in bone studied by small-angle X-ray scattering. Calcif Tiss Int. June 1991;48(6):407-413.
1993	Martin RB, Boardman DL. The effects of collagen fiber orientation, porosity, density, and mineralization on bovine cortical bone bending properties. J Biomech. September 1993;26(9):1047-1054.
1988	Currey JD. The effect of porosity and mineral content on the Young's modulus of elasticity of compact bone. J Biomech. 1988;21(2):131-139.
2003	Carden A, Rajachar RM, Morris MD, Kohn DH. Ultrastructural changes accompanying the mechanical deformation of bone tissue: a Raman imaging study. Calcif Tiss Int. February 2003;72(2):166-175.
1973	Smith DM, Nance WE, Kang KW, Christian JC, Johnston CC Jr. Genetic factors in determining bone mass. J Clin Invest. 1973;52(11):2800-2808.
1988	Alho A, Husby R, Høiseth A. Bone mineral content and mechanical strength: an ex vivo study on human femora at autopsy. Clin Orthop Relat Res. February 1988;227:292-297.
1999	Kodama Y, Dimai HP, Wergedal J, Sheng M, Malpe R, Kutilek S, Beamer W, Donahue LR, Rosen C, Baylink DJ, Farley J. Cortical tibial bone volume in two strains of mice: effects of sciatic neurectomy and genetic regulation of bone response to mechanical loading. Bone. August 1999;25(2):183-190.
1987	Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR. Bone histomorphometry: standardization of nomenclature, symbols, and units: report of the ASBMR histomorphometry nomenclature committee. J Bone Miner Res. December 1987;2(6):595-610.
1997	Currey JD, Foreman J, Laketić I, Mitchell J, Pegg DE, Reilly GC. Effects of ionizing radiation on the mechanical properties of human bone. J Orthop Res. January 1997;15(1):111-117.
2001	Hsieh Y, Robling AG, Ambrosius WT, Burr DB, Turner CH. Mechanical loading of diaphyseal bone in vivo: the strain threshold for an osteogenic response varies with location. J Bone Miner Res. December 2001;16(10):2291-2297.
1993	Turner CH, Burr DB. Basic biomechanical measurements of bone: a tutorial. Bone. 1993;14(4):595-608.
2001	Freeman JJ, Wopenka B, Silva MJ, Pasteris JD. Raman spectroscopic detection of changes in bioapatite in mouse femora as a function of age and in vitro fluoride treatment. Calcif Tiss Int. March 2001;68(3):156-162.
1999	Camacho NP, Hou L, Toledano TR, Ilg WA, Brayton CF, Raggio CL, Root L, Boskey AL. The material basis for reduced mechanical properties in oim mice bones. J Bone Miner Res. February 1999;14(2):264-272.
2003	Boskey A. Bone mineral crystal size. Osteoporos Int. September 2003;14(suppl 5):S16-S20.
2003	Duan Y, Beck TJ, Wang X-F, Seeman E. Structural and biomechanical basis of sexual dimorphism in femoral neck fragility has its origins in growth and aging. J Bone Miner Res. October 2003;18(10):1766-1774.
1987	Pocock NA, Eisman JA, Hopper JL, Yeates MG, Sambrook PN, Eberl S. Genetic determinants of bone mass in adults: a twin study. J Clin Invest. September 1987;80(3):706-710.
2002	Gross TS, Srinivasan S, Liu CC, Clemens TL, Bain SD. Noninvasive loading of the murine tibia: an in vivo model for the study of mechanotransduction. J Bone Miner Res. March 2002;17(3):493-501.
1995	Duncan RL, Turner CH. Mechanotransduction and the functional response of bone to mechanical strain. Calcif Tiss Int. December 1995;57(5):344-358.
2005	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. March 2005;38(3):467-475.
1999	Iwamoto J, Yeh JK, Aloia JF. Differential effect of treadmill exercise on three cancellous bone sites in the young growing rat. Bone. March 1999;24(3):163-169.
1994	Turner CH, Forwood MR, Rho J, Yoshikawa T. Mechanical loading thresholds for lamellar and woven bone formation. J Bone Miner Res. January 1994;9(1):87-97.
1989	Martin RB, Ishida J. The relative effects of collagen fiber orientation, porosity, density, and mineralization on bone strength. J Biomech. 1989;22(5):419-426.
1995	Oxlund H, Barckman M, Ørtoft G, Andreassen TT. Reduced concentrations of collagen cross-links are associated with reduced strength of bone. Bone. October 1995;17(4)(suppl):S365-S371.
2004	Warden SJ, Turner CH. Mechanotransduction in the cortical bone is most efficient at loading frequencies of 5–10 hz. Bone. February 2004;34(2):261-270.
2004	Mullender M, El Haj AJ, Yang Y, van Duin MA, Burger EH, Klein-Nulend J. Mechanotransduction of bone cells in vitro: mechanobiology of bone tissue. Med Biol Eng Comput. January 2004;42(1):14-21.
2004	Kozloff KM, Carden A, Bergwitz C, Forlino A, Uveges TE, Morris MD, Marini JC, Goldstein SA. Brittle IV mouse model for osteogenesis imperfecta IV demonstrates postpubertal adaptations to improve whole bone strength. J Bone Miner Res. April 2004;19(4):614-622.
2006	Garnero P, Borel O, Gineyts E, Duboeuf F, Solberg H, Bouxsein ML, Christiansen C, Delmas PD. Extracellular post-translational modifications of collagen are major determinants of biomechanical properties of fetal bovine cortical bone. Bone. March 2006;38(3):300-309.
2000	Akhter MP, Iwaniec UT, Covey MA, Cullen DM, Kimmel DB, Recker RR. Genetic variations in bone density, histomorphometry, and strength in mice. Calcif Tiss Int. October 2000;67(4):337-344.
2001	Paschalis EP, Verdelis K, Doty SB, Boskey AL, Mendelsohn R, Yamauchi M. Spectroscopic characterization of collagen cross‐links in bone. J Bone Miner Res. October 2001;16(10):1821-1828.
2006	Viguet-Carrin S, Garnero P, Delmas PD. The role of collagen in bone strength. Osteoporos Int. March 2006;17(3):319-336.
1999	Sheng MH-C, Baylink DJ, Beamer WG, Donahue LR, Rosen CJ, Lau K-HW, Wergedal JE. 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. October 1999;25(4):421-429.
1998	Klein RF, Mitchell SR, Phillips TJ, Belknap JK, Orwoll ES. Quantitative trait loci affecting peak bone mineral density in mice. J Bone Miner Res. November 1998;13(11):1648-1656.
2003	Ferguson VL, Ayers RA, Bateman TA, Simske SJ. Bone development and age-related bone loss in male C57BL/6J mice. Bone. March 2003;32(3):387-398.
1997	Burr DB, Forwood MR, Fyhrie DP, Martin RB, Schaffler MB, Turner CH. Bone microdamage and skeletal fragility in osteoporotic and stress fractures. J Bone Miner Res. January 1997;12(1):6-15.
2002	Burr DB. The contribution of the organic matrix to bone's material properties. Bone. July 2002;31(1):8-11.
1975	Burstein AH, Zika JM, Heiple KG, Klein L. Contribution of collagen and mineral to the elastic-plastic properties of bone. J Bone Joint Surg. October 1975;57A(7):956-961.
2000	Kodama Y, Umemura Y, Nagasawa S, Beamer WG, Donahue LR, Rosen CR, Baylink DJ, Farley JR. Exercise and mechanical loading increase periosteal bone formation and whole bone strength in C57BL/6J mice but not in C3H/Hej mice. Calcif Tiss Int. April 2000;66(4):298-306.
1998	Knott L, Bailey AJ. Collagen cross-links in mineralizing tissues: a review of their chemistry, function, and clinical relevance. Bone. March 1998;22(3):181-187.
2003	Rajachar RM. Effects of Age -Related Ultra-Structural Level Changes in Bone on Microdamage Mechanisms [PhD thesis]. University of Michigan; 2003.
2000	Robling AG, Burr DB, Turner CH. Partitioning a daily mechanical stimulus into discrete loading bouts improves the osteogenic response to loading. J Bone Miner Res. August 2000;15(8):1596-1602.
2007	Wallace JM, Rajachar RM, Allen MR, Bloomfield SA, Robey PG, Young MF, Kohn DH. Exercise-induced changes in the cortical bone of growing mice are bone- and gender-specific. Bone. April 2007;40(4):1120-1127.
2004	Follet H, Boivin G, Rumelhart C, Meunier PJ. The degree of mineralization is a determinant of bone strength: a study on human calcanei. Bone. May 2004;34(5):783-789.
2002	Robling AG, Hinant FM, Burr DB, Turner CH. Shorter, more frequent mechanical loading sessions enhance bone mass. Med Sci Sports Exer. February 2002;34(2):196-202.
2002	Robling AG, Turner CH. Mechanotransduction in bone: genetic effects on mechanosensitivity in mice. Bone. November 2002;31(5):562-569.
1998	Rho J-Y, Kuhn-Spearing L, Zioupos P. Mechanical properties and the hierarchical structure of bone. Med Eng Phys. 1998;20(2):92-102.

Year

Entry

2002

Wang X, Li X, Bank RA, Agrawal CM. Effects of collagen unwinding and cleavage on the mechanical integrity of the collagen network in bone. Calcif Tiss Int. August 2002;71(2):186-192.

2004

Ward K, Alsop C, Caulton J, Rubin C, Adams J, Mughal Z. Low magnitude mechanical loading is osteogenic in children with disabling conditions. J Bone Miner Res. March 2004;19(3):360-369.

1999

Timlin JA, Carden A, Morris MD. Chemical microstructure of cortical bone probed by Raman transects. Appl Spectrosc. November 1999;53(11):1429-1435.

1993

Biewener AA. Safety factors in bone strength. Calcif Tiss Int. February 1993;53(suppl 1):S68-S74.

2000

Timlin JA, Carden A, Morris MD, Rajachar RM, Kohn DH. Raman spectroscopic imaging markers for fatigue-related microdamage in bovine bone. Anal Chem. May 15, 2000;72(10):2229-2236.

2004

Somerville JM, Aspden RM, Armour KE, Armour KJ, Reid DM. Growth of C57Bl/6 mice and the material and mechanical properties of cortical bone from the tibia. Calcif Tiss Int. May 2004;74(5):469-475.

1999

Boskey AL, Wright TM, Blank RD. Collagen and bone strength. J Bone Miner Res. March 1999;14(3):330-335.

1995

Landis WJ. The strength of a calcified tissue depends in part on the molecular structure and organization of its constituent mineral crystals in their organic matrix. Bone. May 1995;16(5):533-544.

2004

Rubin C, Recker R, Cullen D, Ryaby J, McCabe J, McLeod K. Prevention of postmenopausal bone loss by a low‐magnitude, high‐frequency mechanical stimuli: a clinical trial assessing compliance, efficacy, and safety. J Bone Miner Res. March 2004;19(3):343-351.

1997

Umemura Y, Ishiko T, Yamauchi T, Kurono M, Mashiko S. Five jumps per day increase bone mass and breaking force in rats. J Bone Miner Res. September 1997;12(10):1480-1485.

2002

Wachter NJ, Krischak GD, Mentzel M, Sarkar MR, Ebinger T, Kinz L, Claes L, Augat P. Correlation of bone mineral density with strength and microstructural parameters of cortical bone in vitro. Bone. July 2002;31(1):90-95.

2001

Turner CH, Hsieh Y, Müller R, Bouxsein ML, Rosen CJ, McCrann ME, Donahue LR, Beamer WG. Variation in bone biomechanical properties, microstructure, and density in BXH recombinant inbred mice. J Bone Miner Res. February 2001;16(2):206-213.

2001

NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. February 14, 2001;285(6):785-795.

2000

Heaney RP, Abrams S, Dawson-Hughes B, Looker A, Marcus R, Matkovic V, Weaver C. Peak bone mass. Osteoporos Int. December 2000;11(12):985-1009.

1998

Akhter MP, Cullen DM, Pedersen EA, Kimmel DB, Recker RR. Bone response to in vivo mechanical loading in two breeds of mice. Calcif Tiss Int. November 1998;63(5):442-449.

1994

Roach HI. Why does bone matrix contain non‐collagenous proteins? the possible roles of osteocalcin, osteonectin, osteopontin and bone sialoprotein in bone mineralisation and resorption. Cell Biol Int. 1994;18(6):617-628.

2000

Turner CH, Hsieh Y, Müller R, Bouxsein ML, Baylink DJ, Rosen CJ, Grynpas MD, Donahue LR, Beamer WG. Genetic regulation of cortical and trabecular bone strength and microstructure in inbred strains of mice. J Bone Miner Res. June 2000;15(6):1126-1131.

2003

Amblard D, Lafage-Proust M-H, Laib A, Thomas T, Rüegsegger P, Alexandre C, Vico L. 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. March 2003;18(3):561-569.

1989

Jones BH, Harris JM, Vinh TN, Rubin C. Exercise-induced stress fractures and stress reactions of bone: epidemiology, etiology, and classification. Exerc Sport Sci Rev. January 1989;17(1):379-422.

1990

Kuhn JL, Goldstein SA, Feldkamp LA, Goulet RW, Jesion G. Evaluation of a microcomputed tomography system to study trabecular bone structure. J Orthop Res. 1990;8(6):833-842.

2005

Nyman JS, Reyes M, Wang X. Effect of ultrastructural changes on the toughness of bone. Micron. October–December 2005;36(7-8):566-582.

2004

Akkus O, Adar F, Schaffler MB. Age-related changes in physicochemical properties of mineral crystals are related to impaired mechanical function of cortical bone. Bone. March 2004;34(4):443-453.

1996

Carter DR, Van der Meulen MCH, Beaupré GS. Mechanical factors in bone growth and development. Bone. January 1996;18(1)(suppl 1):S5-S10.

1998

Weiner S, Wagner HD. The material bone: structure-mechanical function relations. Ann Rev Mater Sci. August 1998;28:271-298.

1996

Gustafson MB, Martin RB, Gibson V, Storms DH, Stover SM, Gibeling J, Griffin L. Calcium buffering is required to maintain bone stiffness in saline solution. J Biomech. September 1996;29(9):1191-1194.

1999

Burger EH, Klein-Nulend J. Mechanotransduction in bone: role of the lacunocanalicular network. FASEB J. May 1999;12(9001):S101-S112.

2001

Rubin C, Turner AS, Bain S, Mallinckrodt C, McLeod K. Low mechanical signals strengthen long bones. Nature. August 9, 2001;412(6847):603-604.

1992

Weiner S, Traub W. Bone structure: from ȧngstroms to microns. FASEB J. February 1992;6(3):879-885.

1999

Adami S, Gatti D, Braga V, Bianchini D, Rossini M. Site-specific effects of strength training on bone structure and geometry of ultradistal radius in postmenopausal women. J Bone Miner Res. January 1999;14(1):120-124.

2005

De Souza RL, Matsuura M, Eckstein F, Rawlinson SCF, Lanyon LE, Pitsillides AA. 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. December 2005;37(6):810-818.

1996

Beamer WG, Donahue LR, Rosen CJ, Baylink DJ. Genetic variability in adult bone density among inbred strains of mice. Bone. May 1996;18(5):397-403.

2002

Wang X, Shen X, Li X, Agrawal CM. Age-related changes in the collagen network and toughness of bone [published correction appears in Bone. 2003;32(1):107]. Bone. 2002;31(1):1-7.

2001

Wang X, Bank RA, Tekoppele JM, Agrawal CM. The role of collagen in determining bone mechanical properties. J Orthop Res. 2001;19(6):1021-1026.

2001

Jepsen KJ, Pennington DE, Lee Y, Warman M, Nadeau J. Bone brittleness varies with genetic background in A/J and C57BL/6J inbred mice. J Bone Miner Res. October 2001;16(10):1854-1862.

1991

Fratzl P, Fratzl-Zelman N, Klaushofer K, Vogl G, Koller K. Nucleation and growth of mineral crystals in bone studied by small-angle X-ray scattering. Calcif Tiss Int. June 1991;48(6):407-413.

1993

Martin RB, Boardman DL. The effects of collagen fiber orientation, porosity, density, and mineralization on bovine cortical bone bending properties. J Biomech. September 1993;26(9):1047-1054.

1988

Currey JD. The effect of porosity and mineral content on the Young's modulus of elasticity of compact bone. J Biomech. 1988;21(2):131-139.

2003

Carden A, Rajachar RM, Morris MD, Kohn DH. Ultrastructural changes accompanying the mechanical deformation of bone tissue: a Raman imaging study. Calcif Tiss Int. February 2003;72(2):166-175.

1973

Smith DM, Nance WE, Kang KW, Christian JC, Johnston CC Jr. Genetic factors in determining bone mass. J Clin Invest. 1973;52(11):2800-2808.

1988

Alho A, Husby R, Høiseth A. Bone mineral content and mechanical strength: an ex vivo study on human femora at autopsy. Clin Orthop Relat Res. February 1988;227:292-297.

1999

Kodama Y, Dimai HP, Wergedal J, Sheng M, Malpe R, Kutilek S, Beamer W, Donahue LR, Rosen C, Baylink DJ, Farley J. Cortical tibial bone volume in two strains of mice: effects of sciatic neurectomy and genetic regulation of bone response to mechanical loading. Bone. August 1999;25(2):183-190.

1987

Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR. Bone histomorphometry: standardization of nomenclature, symbols, and units: report of the ASBMR histomorphometry nomenclature committee. J Bone Miner Res. December 1987;2(6):595-610.

1997

Currey JD, Foreman J, Laketić I, Mitchell J, Pegg DE, Reilly GC. Effects of ionizing radiation on the mechanical properties of human bone. J Orthop Res. January 1997;15(1):111-117.

2001

Hsieh Y, Robling AG, Ambrosius WT, Burr DB, Turner CH. Mechanical loading of diaphyseal bone in vivo: the strain threshold for an osteogenic response varies with location. J Bone Miner Res. December 2001;16(10):2291-2297.

1993

Turner CH, Burr DB. Basic biomechanical measurements of bone: a tutorial. Bone. 1993;14(4):595-608.

2001

Freeman JJ, Wopenka B, Silva MJ, Pasteris JD. Raman spectroscopic detection of changes in bioapatite in mouse femora as a function of age and in vitro fluoride treatment. Calcif Tiss Int. March 2001;68(3):156-162.

1999

Camacho NP, Hou L, Toledano TR, Ilg WA, Brayton CF, Raggio CL, Root L, Boskey AL. The material basis for reduced mechanical properties in oim mice bones. J Bone Miner Res. February 1999;14(2):264-272.

2003

Boskey A. Bone mineral crystal size. Osteoporos Int. September 2003;14(suppl 5):S16-S20.

2003

Duan Y, Beck TJ, Wang X-F, Seeman E. Structural and biomechanical basis of sexual dimorphism in femoral neck fragility has its origins in growth and aging. J Bone Miner Res. October 2003;18(10):1766-1774.

1987

Pocock NA, Eisman JA, Hopper JL, Yeates MG, Sambrook PN, Eberl S. Genetic determinants of bone mass in adults: a twin study. J Clin Invest. September 1987;80(3):706-710.

2002

Gross TS, Srinivasan S, Liu CC, Clemens TL, Bain SD. Noninvasive loading of the murine tibia: an in vivo model for the study of mechanotransduction. J Bone Miner Res. March 2002;17(3):493-501.

1995

Duncan RL, Turner CH. Mechanotransduction and the functional response of bone to mechanical strain. Calcif Tiss Int. December 1995;57(5):344-358.

2005

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. March 2005;38(3):467-475.

1999

Iwamoto J, Yeh JK, Aloia JF. Differential effect of treadmill exercise on three cancellous bone sites in the young growing rat. Bone. March 1999;24(3):163-169.

1994

Turner CH, Forwood MR, Rho J, Yoshikawa T. Mechanical loading thresholds for lamellar and woven bone formation. J Bone Miner Res. January 1994;9(1):87-97.

1989

Martin RB, Ishida J. The relative effects of collagen fiber orientation, porosity, density, and mineralization on bone strength. J Biomech. 1989;22(5):419-426.

1995

Oxlund H, Barckman M, Ørtoft G, Andreassen TT. Reduced concentrations of collagen cross-links are associated with reduced strength of bone. Bone. October 1995;17(4)(suppl):S365-S371.

2004

Warden SJ, Turner CH. Mechanotransduction in the cortical bone is most efficient at loading frequencies of 5–10 hz. Bone. February 2004;34(2):261-270.

2004

Mullender M, El Haj AJ, Yang Y, van Duin MA, Burger EH, Klein-Nulend J. Mechanotransduction of bone cells in vitro: mechanobiology of bone tissue. Med Biol Eng Comput. January 2004;42(1):14-21.

2004

Kozloff KM, Carden A, Bergwitz C, Forlino A, Uveges TE, Morris MD, Marini JC, Goldstein SA. Brittle IV mouse model for osteogenesis imperfecta IV demonstrates postpubertal adaptations to improve whole bone strength. J Bone Miner Res. April 2004;19(4):614-622.

2006

Garnero P, Borel O, Gineyts E, Duboeuf F, Solberg H, Bouxsein ML, Christiansen C, Delmas PD. Extracellular post-translational modifications of collagen are major determinants of biomechanical properties of fetal bovine cortical bone. Bone. March 2006;38(3):300-309.

2000

Akhter MP, Iwaniec UT, Covey MA, Cullen DM, Kimmel DB, Recker RR. Genetic variations in bone density, histomorphometry, and strength in mice. Calcif Tiss Int. October 2000;67(4):337-344.

2001

Paschalis EP, Verdelis K, Doty SB, Boskey AL, Mendelsohn R, Yamauchi M. Spectroscopic characterization of collagen cross‐links in bone. J Bone Miner Res. October 2001;16(10):1821-1828.

2006

Viguet-Carrin S, Garnero P, Delmas PD. The role of collagen in bone strength. Osteoporos Int. March 2006;17(3):319-336.

1999

Sheng MH-C, Baylink DJ, Beamer WG, Donahue LR, Rosen CJ, Lau K-HW, Wergedal JE. 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. October 1999;25(4):421-429.

1998

Klein RF, Mitchell SR, Phillips TJ, Belknap JK, Orwoll ES. Quantitative trait loci affecting peak bone mineral density in mice. J Bone Miner Res. November 1998;13(11):1648-1656.

2003

Ferguson VL, Ayers RA, Bateman TA, Simske SJ. Bone development and age-related bone loss in male C57BL/6J mice. Bone. March 2003;32(3):387-398.

1997

Burr DB, Forwood MR, Fyhrie DP, Martin RB, Schaffler MB, Turner CH. Bone microdamage and skeletal fragility in osteoporotic and stress fractures. J Bone Miner Res. January 1997;12(1):6-15.

2002

Burr DB. The contribution of the organic matrix to bone's material properties. Bone. July 2002;31(1):8-11.

1975

Burstein AH, Zika JM, Heiple KG, Klein L. Contribution of collagen and mineral to the elastic-plastic properties of bone. J Bone Joint Surg. October 1975;57A(7):956-961.

2000

Kodama Y, Umemura Y, Nagasawa S, Beamer WG, Donahue LR, Rosen CR, Baylink DJ, Farley JR. Exercise and mechanical loading increase periosteal bone formation and whole bone strength in C57BL/6J mice but not in C3H/Hej mice. Calcif Tiss Int. April 2000;66(4):298-306.

1998

Knott L, Bailey AJ. Collagen cross-links in mineralizing tissues: a review of their chemistry, function, and clinical relevance. Bone. March 1998;22(3):181-187.

2003

Rajachar RM. Effects of Age -Related Ultra-Structural Level Changes in Bone on Microdamage Mechanisms [PhD thesis]. University of Michigan; 2003.

2000

Robling AG, Burr DB, Turner CH. Partitioning a daily mechanical stimulus into discrete loading bouts improves the osteogenic response to loading. J Bone Miner Res. August 2000;15(8):1596-1602.

2007

Wallace JM, Rajachar RM, Allen MR, Bloomfield SA, Robey PG, Young MF, Kohn DH. Exercise-induced changes in the cortical bone of growing mice are bone- and gender-specific. Bone. April 2007;40(4):1120-1127.

2004

Follet H, Boivin G, Rumelhart C, Meunier PJ. The degree of mineralization is a determinant of bone strength: a study on human calcanei. Bone. May 2004;34(5):783-789.

2002

Robling AG, Hinant FM, Burr DB, Turner CH. Shorter, more frequent mechanical loading sessions enhance bone mass. Med Sci Sports Exer. February 2002;34(2):196-202.

2002

Robling AG, Turner CH. Mechanotransduction in bone: genetic effects on mechanosensitivity in mice. Bone. November 2002;31(5):562-569.

1998

Rho J-Y, Kuhn-Spearing L, Zioupos P. Mechanical properties and the hierarchical structure of bone. Med Eng Phys. 1998;20(2):92-102.

Year	Entry
2009	Wallace JM, Golcuk K, Morris MD, Kohn DH. Inbred strain-specific response to biglycan deficiency in the cortical bone of C57BL6/129 and C3H/He mice. J Bone Miner Res. June 2009;24(6):1002-1012.

Year

Entry

2009

Wallace JM, Golcuk K, Morris MD, Kohn DH. Inbred strain-specific response to biglycan deficiency in the cortical bone of C57BL6/129 and C3H/He mice. J Bone Miner Res. June 2009;24(6):1002-1012.