Microscopic damage is the microstructural consequence of wear and tear (i.e., fatigue) in bone. Bone remodeling can repair the typical linear microcracks that have been reported in bone, and this capability is essential for maintenance of its mechanical integrity. However, recent studies demonstrate that linear microcracks are just one of a range of matrix damage types that result from fatigue in bone. Most other matrix damage processes cause "small crack"-type damage, which are collectively referred to as "diffuse" damage. Diffuse damage is widely observed in the aging skeleton, and like typical linear microcracks it degrades bone material properties, yet the relevance of diffuse damage to bone physiology is not known. Our preliminary studies show that diffuse damage does not activate bone remodeling as do typical microcracks, nor does it cause the local osteocyte apoptosis now known to control the subsequent remodeling response. Rather, osteocytes at diffuse damage sites appear to remain quite healthy. In view of recent discoveries showing osteocytes actively regulate their surrounding matrix, particularly by regulating local mineral deposition, we propose that bone possesses a matrix level "self-repair" mechanism that is distinct from osteoclast-based remodeling. In this process, small ("diffuse") crack damage undergoes direct repair through the actions of osteocytes. We will use the rat in vivo ulnar bending fatigue model to address this question in vivo. In the first studies, discrete regions of diffuse matrix damage will be induced. Changes in the mechanical properties of local regions of diffuse damage and of corresponding areas in non-fatigued bone will be measured using Scanning Acoustic Microscopy. Quantitative back-scattered imaging will be used to examine mineral matrix integrity and the local mineral content in diffuse damage regions, and Raman spectroscopy used to characterize crystal size and mineral and organic composition. In the second series of studies, we will determine whether fatigue selectively elicits changes in the expression of local mineralization-regulating molecules by osteocytes within diffuse damage sites, consistent with a restore local matrix mineral integrity in diffuse damage regions.

Public Health Relevance

It has long been known that bone remodeling can remove and repair the typical microscopic (~100 5m size) cracks that result from wear and tear (i.e., mechanical fatigue) in bone, and thereby help restore strength and prevent fracture. However, there are other types of fatigue damage in the matrix of bone, comprised of much smaller cracks (1-2 5m or smaller) that also weaken bone substantially. We recently discovered that these small cracks are not dealt with by bone remodeling. Thus, their healing must involve other biological mechanisms. In these studies, we will test whether these very small cracks in bone can heal over time through another mechanism than does not involve bone remodeling, and we will also examine how osteocytes, the bone cells that live buried within the bone matrix, might participate in the direct repair of these very small cracks and prevent bone fragility.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AR060445-02
Application #
8206602
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Chen, Faye H
Project Start
2011-01-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
2
Fiscal Year
2012
Total Cost
$168,071
Indirect Cost
$55,571
Name
City College of New York
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
603503991
City
New York
State
NY
Country
United States
Zip Code
10031
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Seref-Ferlengez, Zeynep; Basta-Pljakic, Jelena; Kennedy, Oran D et al. (2014) Structural and mechanical repair of diffuse damage in cortical bone in vivo. J Bone Miner Res 29:2537-44
Cheung, Wing-Yee; Kennedy, Oran D; Majeska, Robert J et al. (2014) Authors response to letter from Plotkin and Bellido. Calcif Tissue Int 95:384
Schaffler, Mitchell B; Cheung, Wing-Yee; Majeska, Robert et al. (2014) Osteocytes: master orchestrators of bone. Calcif Tissue Int 94:5-24
Wu, Danielle; Schaffler, Mitchell B; Weinbaum, Sheldon et al. (2013) Matrix-dependent adhesion mediates network responses to physiological stimulation of the osteocyte cell process. Proc Natl Acad Sci U S A 110:12096-101
Kennedy, Oran D; Herman, Brad C; Laudier, Damien M et al. (2012) Activation of resorption in fatigue-loaded bone involves both apoptosis and active pro-osteoclastogenic signaling by distinct osteocyte populations. Bone 50:1115-22
Schaffler, Mitchell B; Kennedy, Oran D (2012) Osteocyte signaling in bone. Curr Osteoporos Rep 10:118-25