One of the primary risk factors associated with osteoporotic fractures is the failure to achieve sufficient bone mass during early adulthood. Exercise holds substantial potential for non-invasive bone accretion, but general exercise protocols only minimally enhance bone mass over normal levels and rely upon high impact, high magnitude loading to achieve these bone gains. Recently, we found that inserting a brief rest interval between each load cycle of a low magnitude loading regimen is sufficient to transform the protocol from one that does not influence bone cell populations into a signal that is potently osteogenic. This regimen may therefore be particularly amenable to application in conditions where enhanced bone properties are desirable, but high impact exercise is not feasible. Based upon our preliminary data and a review of the literature, we hypothesize that low magnitude, rest-inserted, mechanical loading initiated during skeletal growth will enhance the cortical bone properties of adult mammals. To explore this hypothesis, we will capitalize on our recently developed non-invasive murine tibia loading device. A series of five Specific Aims have been designed to determine if rest-inserted, low magnitude loading can serve to build and maintain augmented tibial cortical bone properties in female C57BLI6J mice. The studies culminate with our final Aim, in which we will assess whether enhanced cortical bone properties induced by the rest-inserted loading are sufficient to counteract the degradation caused by aging and estrogen depletion. At a basic level, these studies will provide unique insight toward how young growing bones respond to mechanical loading, and will provide a baseline of information from which we will, in the future, begin to explore how specific genetic alterations (e.g., via transgenic or knockout mice) affect mechanotransduction in bone. At the applied level, an outcome in which rest-inserted, low magnitude, non-invasive loading significantly augments and maintains murine cortical bone properties would place our group in position to begin to explore the efficacy of this concept in human subjects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR048102-03
Application #
6632742
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Sharrock, William J
Project Start
2001-04-01
Project End
2005-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
3
Fiscal Year
2003
Total Cost
$273,486
Indirect Cost
Name
University of Washington
Department
Orthopedics
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Poliachik, Sandra L; Threet, DeWayne; Srinivasan, Sundar et al. (2008) 32 wk old C3H/HeJ mice actively respond to mechanical loading. Bone 42:653-9
Srinivasan, Sundar; Ausk, Brandon J; Poliachik, Sandra L et al. (2007) Rest-inserted loading rapidly amplifies the response of bone to small increases in strain and load cycles. J Appl Physiol 102:1945-52
Rubin, Janet; Schwartz, Zvi; Boyan, Barbara D et al. (2007) Caveolin-1 knockout mice have increased bone size and stiffness. J Bone Miner Res 22:1408-18
Ausk, Brandon J; Gross, Ted S; Srinivasan, Sundar (2006) An agent based model for real-time signaling induced in osteocytic networks by mechanical stimuli. J Biomech 39:2638-46
Hankenson, Kurt D; Ausk, Brandon J; Bain, Steven D et al. (2006) Mice lacking thrombospondin 2 show an atypical pattern of endocortical and periosteal bone formation in response to mechanical loading. Bone 38:310-6
Gross, Ted S; Poliachik, Sandra L; Ausk, Brandon J et al. (2004) Why rest stimulates bone formation: a hypothesis based on complex adaptive phenomenon. Exerc Sport Sci Rev 32:9-13
Srinivasan, Sundar; Agans, Stephen C; King, Katy A et al. (2003) Enabling bone formation in the aged skeleton via rest-inserted mechanical loading. Bone 33:946-55
Gross, Ted S; Srinivasan, Sundar; Liu, Chung C et al. (2002) Noninvasive loading of the murine tibia: an in vivo model for the study of mechanotransduction. J Bone Miner Res 17:493-501
Srinivasan, Sundar; Weimer, David A; Agans, Steven C et al. (2002) Low-magnitude mechanical loading becomes osteogenic when rest is inserted between each load cycle. J Bone Miner Res 17:1613-20