In part to explore the specific signaling pathways that underlie the co-dependency between muscle and bone, we have developed a novel in vivo murine model of transient muscle paralysis that inhibits both motor and sensory signaling following intramuscular injections of botulinum toxin A (BTxA). Despite a mild and transient gait deficit, we have shown that the loss of trabecular bone following transient muscle paralysis is rapid and profound and dominated by RANKL mediated osteoclastic resorption. Our preliminary data with a mouse hindlimb specific defect in proprioception has led us to hypothesize that trabecular bone homeostasis is modulated by neuromuscular proprioception. In this project we will pursue this thesis through four closely related sub-hypotheses each with a corresponding Specific Aim. The first three S.
Aims seek to demonstrate that while mechanical stimuli clearly influence trabecular bone homeostasis, muscle proprioception plays a previously unrecognized, but fundamental role in modulating local trabecular bone morphology. In the final S.
Aim we will attempt to clarify that a neuronally mediated inflammatory response precedes and mediates the profound osteoclastic resorption acutely induced by transient muscle paralysis. If these data support our hypothesis, we believe that our results hold potential to alter current approaches to intervene or prevent bone loss in a variety of musculoskeletal pathologies.

Public Health Relevance

This project seeks to elucidate a fundamental, but as yet unrecognized neuronal pathway by which normal trabecular bone homeostasis is achieved and maintained. From a clinical perspective, we believe that understanding the role that sensory proprioception plays in modulating local trabecular bone homeostasis will directly enable novel interventions into both acute (e.g., spinal cord injury, general disuse) and chronic (e.g., associated with aging) bone loss pathologies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR060304-04
Application #
8513924
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Sharrock, William J
Project Start
2010-09-20
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$320,112
Indirect Cost
$114,912
Name
University of Washington
Department
Orthopedics
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Avin, Keith G; Bloomfield, Susan A; Gross, Ted S et al. (2015) Biomechanical aspects of the muscle-bone interaction. Curr Osteoporos Rep 13:8-Jan
Ausk, Brandon J; Huber, Philippe; Srinivasan, Sundar et al. (2013) Metaphyseal and diaphyseal bone loss in the tibia following transient muscle paralysis are spatiotemporally distinct resorption events. Bone 57:413-22
Moustafa, A; Sugiyama, T; Prasad, J et al. (2012) Mechanical loading-related changes in osteocyte sclerostin expression in mice are more closely associated with the subsequent osteogenic response than the peak strains engendered. Osteoporos Int 23:1225-34
Aliprantis, Antonios O; Stolina, Marina; Kostenuik, Paul J et al. (2012) Transient muscle paralysis degrades bone via rapid osteoclastogenesis. FASEB J 26:1110-8
Ausk, Brandon J; Huber, Philippe; Poliachik, Sandra L et al. (2012) Cortical bone resorption following muscle paralysis is spatially heterogeneous. Bone 50:14-22