Skeletal mass and load-bearing capacity diminish with aging and the associated hormonal and metabolic changes, contributing to skeletal fractures at corticocancellous sites. Biophysical stimuli may be an effective therapy to counter age-related changes in bone mass, structure and strength. Dynamic mechanical loading is known to regulate skeletal mass and structure. However, little is known about the mechanisms of cancellous bone adaptation to mechanical stimuli, as our the majority of our knowledge of loading and bone formation is based on cortical adaptation. Our overall goal is to test the hypothesis that in vivo cyclic mechanical loading applied to cancellous bone counteracts the osteopenia induced by estrogen withdrawal and aging. To test this hypothesis we have developed a loading device to administer well-controlled physiological compression to the mouse tibia in vivo. Increased cancellous bone mass is produced in the tibial metaphysis of healthy mice with this physiological loading. We now propose to examine the interaction of mechanical loading with estrogen-deficiency and aging.
In Aim 1, we will apply controlled mechanical loads to the tibiae of 10-week old mice following ovariectomy. Our loading protocol will be identical to that used for our preliminary studies.
For Aim 2, we will apply controlled mechanical loads to 6-month old mice and demonstrate that osteogenic mechanical stimuli will induce bone formation in adult mice in the presence of estrogen. These older mice will already be osteopenic and, therefore, also demonstrate that tissue substrate surface is not the limiting factor in responding to mechanical loading. Finally, in Aim 3, we will examine whether estrogen-deficiency reduces the sensitivity of 6-month old mice to osteogenic loading. For each aim, long-term experiments will demonstrate the steady-state adaptive response and short-term experiments will focus on the cellular mechanisms. Cancellous architecture, material properties, cellular activity and load bearing capacity will be assessed in the tibial metaphysis. Combined, these experiments will demonstrate the efficacy of dynamic mechanical loads for maintaining and enhancing cancellous bone mass and the role of estrogen in this process. These experiments will provide insights into the mechanisms whereby cancellous bone adapts to mechanical loading and into strategies for inhibiting age-related and postmenopausal bone loss. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG028664-01
Application #
7132726
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Dutta, Chhanda
Project Start
2006-09-01
Project End
2010-05-31
Budget Start
2006-09-01
Budget End
2007-05-31
Support Year
1
Fiscal Year
2006
Total Cost
$271,127
Indirect Cost
Name
Cornell University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Kelly, Natalie H; Schimenti, John C; Ross, F Patrick et al. (2016) Transcriptional profiling of cortical versus cancellous bone from mechanically-loaded murine tibiae reveals differential gene expression. Bone 86:22-9
Ko, Frank C; Dragomir, Cecilia L; Plumb, Darren A et al. (2016) Progressive cell-mediated changes in articular cartilage and bone in mice are initiated by a single session of controlled cyclic compressive loading. J Orthop Res 34:1941-1949
Holyoak, Derek T; Tian, Ye F; van der Meulen, Marjolein C H et al. (2016) Osteoarthritis: Pathology, Mouse Models, and Nanoparticle Injectable Systems for Targeted Treatment. Ann Biomed Eng 44:2062-75
Melville, Katherine M; Robling, Alexander G; van der Meulen, Marjolein C H (2015) In vivo axial loading of the mouse tibia. Methods Mol Biol 1226:99-115
Melville, Katherine M; Kelly, Natalie H; Surita, Gina et al. (2015) Effects of Deletion of ER? in Osteoblast-Lineage Cells on Bone Mass and Adaptation to Mechanical Loading Differ in Female and Male Mice. J Bone Miner Res 30:1468-80
Morse, A; McDonald, M M; Kelly, N H et al. (2014) Mechanical load increases in bone formation via a sclerostin-independent pathway. J Bone Miner Res 29:2456-67
Melville, Katherine M; Kelly, Natalie H; Khan, Sohaib A et al. (2014) Female mice lacking estrogen receptor-alpha in osteoblasts have compromised bone mass and strength. J Bone Miner Res 29:370-9
Main, Russell P; Lynch, Maureen E; van der Meulen, Marjolein C H (2014) Load-induced changes in bone stiffness and cancellous and cortical bone mass following tibial compression diminish with age in female mice. J Exp Biol 217:1775-83
Kelly, Natalie H; Schimenti, John C; Patrick Ross, F et al. (2014) A method for isolating high quality RNA from mouse cortical and cancellous bone. Bone 68:1-5
Yang, Xu; Willie, Bettina M; Beach, Jocelyn M et al. (2013) Trabecular bone adaptation to loading in a rabbit model is not magnitude-dependent. J Orthop Res 31:930-4

Showing the most recent 10 out of 20 publications