We will apply solid-state magic angle spinning nuclear magnetic resonance spectroscopy (MAS-NMR) to measure changes in the chemical structure of bone tissue under mechanical load. MAS-NMR will allow us to examine ultrastructure contributions to bone quality that have, to date, been unobtainable using traditional imaging techniques or other biophysical techniques. The enabling advance is a special NMR cell that allows compressive loading and displacement measurements. High-resolution structural information will be correlated to strain of bone tissue from mature murine tibiae as the specimens are deformed under uniaxial compression.
In Aim 1 we will assess distortion of the bone mineral lattice as changes in the mineral ion spacings and water mobility using a several different 1D and 2D solid-state NMR pulse sequences. We will also study load- induced changes in a series of synthesized carbonated apatites, which are model compounds for bone mineral to guide interpretation of our bone mineral results and to enable measurements with isotopically enriched nuclei, especially 43Ca. In these simplified model compounds we can accurately measure inter-ion distances, movement of mineral impurities, and reorganization of local symmetry and resolve uncertainties in the measurements of the more complex biomineral.
In Aim 2 we will investigate the role of water in stabilizing both the mineral and matrix components via hydrogen bonding and enthalpic stabilization. Changes in collagen secondary structure will be measured through 13C resonances. We will use a unique protocol for controlled disordering of the collagen and mineral by partial and complete displacement of native matrix water with deuterium oxide, which forms weaker hydrogen bonds. NMR will probe water bridges and glycine-proline bonds, as well as mineral changes, with correlations to measured strain and applied load.
In Aim 3 we will examine the loading response of mineral deformation, collagen conformation changes and hydrogen bonding in native and damaged bone tissue from mice of various ages in order to understand how age-related changes in the mineral and matrix compromise the mechanical competence of bone tissue. Controlled partial replacement of hydrogen ion with deuterium ion will be used to provide a range of collagen conformation changes.

Public Health Relevance

Fragility fractures are a major health threat in aging populations and understanding the factors that contribute to bone failure is vitally important to the development of new interventional approaches. Through the development of methods for measuring NMR spectra of bone under compressive load, this project, for the first time, brings to this problem the power of solid-state nuclear magnetic resonance spectroscopy to understand the changes in bone structure when subjected to mechanical loading.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR056657-03
Application #
8268927
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Sharrock, William J
Project Start
2010-08-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$328,046
Indirect Cost
$101,360
Name
University of Michigan Ann Arbor
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Mroue, Kamal H; Xu, Jiadi; Zhu, Peizhi et al. (2016) Selective detection and complete identification of triglycerides in cortical bone by high-resolution (1)H MAS NMR spectroscopy. Phys Chem Chem Phys 18:18687-91
Gardinier, Joseph D; Al-Omaishi, Salam; Morris, Michael D et al. (2016) PTH signaling mediates perilacunar remodeling during exercise. Matrix Biol 52-54:162-75
Iura, Ayaka; McNerny, Erin Gatenby; Zhang, Yanshuai et al. (2015) Mechanical Loading Synergistically Increases Trabecular Bone Volume and Improves Mechanical Properties in the Mouse when BMP Signaling Is Specifically Ablated in Osteoblasts. PLoS One 10:e0141345
Gardinier, Joseph D; Mohamed, Fatma; Kohn, David H (2015) PTH Signaling During Exercise Contributes to Bone Adaptation. J Bone Miner Res 30:1053-63
Maeda, Azusa; Ono, Mitsuaki; Holmbeck, Kenn et al. (2015) WNT1-induced Secreted Protein-1 (WISP1), a Novel Regulator of Bone Turnover and Wnt Signaling. J Biol Chem 290:14004-18
Mroue, Kamal H; Nishiyama, Yusuke; Kumar Pandey, Manoj et al. (2015) Proton-Detected Solid-State NMR Spectroscopy of Bone with Ultrafast Magic Angle Spinning. Sci Rep 5:11991
McNerny, Erin M B; Gardinier, Joseph D; Kohn, David H (2015) Exercise increases pyridinoline cross-linking and counters the mechanical effects of concurrent lathyrogenic treatment. Bone 81:327-37
McNerny, Erin M B; Gong, Bo; Morris, Michael D et al. (2015) Bone fracture toughness and strength correlate with collagen cross-link maturity in a dose-controlled lathyrism mouse model. J Bone Miner Res 30:455-64
Mroue, Kamal H; Zhang, Rongchun; Zhu, Peizhi et al. (2014) Acceleration of natural-abundance solid-state MAS NMR measurements on bone by paramagnetic relaxation from gadolinium-DTPA. J Magn Reson 244:90-7
Tchanque-Fossuo, Catherine N; Gong, Bo; Poushanchi, Behdod et al. (2013) Raman spectroscopy demonstrates Amifostine induced preservation of bone mineralization patterns in the irradiated murine mandible. Bone 52:712-7

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