It is postulated that osteonal remodeling serves to remove and replace regions of compact bone which accumulate microdamage due to fatigue. However, little is known about the damage or remodeling responses which occur at the levels of fatigue expected to result from normal wear and tear. How bone remodeling units """"""""target"""""""" microscopically damaged areas of bone is unknown. Effective targeting and removal of damaged bone is essential for maintaining skeletal integrity. Recent data indicates that ultrastructural-level bone matrix damage dominates the early fatigue process in human bone, rather than the typical linear microcracks which have been widely thought to represent primary fatigue process. The role of this predominant fatigue damage mode on activation of intracortical remodeling processes is currently unexplored. Using our modification of the ulnar bending model of Torrance et al (112), adult rat ulnae can be fatigued in vivo, to initiate intracortical resorption activity. Studies also suggest that decreased osteocyte viability occurs with fatigue and injury, and that areas of altered osteocyte integrity can be associated with intracortical resorption, independent Of microdamage. The proposed studies will examine a) whether early, ultrastructural level fatigue damage in bone initiate intracortical remodeling, b) how bone fatigue affects osteocyte integrity, and c) whether changes in osteocyte integrity are a determinant of intracortical remodeling. Specifically, we will use the rat ulnar fatigue model for three interrelated experiments: 1) In vivo fatigue loading, combined with confocal microscopy and bone histomorphometry will be used to determine temporal and spatial associations of matrix-level damage processes with intracortical remodeling. 2) We will determine the specific associations of bone matrix microdamage and osteocyte viability or osteocyte injury/loss of viability, and examine the mechanism by which osteocyte degeneration occurs in fatigue loaded bone. Osteocyte integrity relative to local bone damage state will be assessed using a newly developed methods for in situ detection of osteocyte viability (versus injured, nonviable cells). A combination of in situ cytochemical staining techniques and electron microscopy will be used secondarily to assess the mechanism of osteocyte degeneration. A specific focus will be on the question of whether apoptosis is characteristic of the response of osteocytes to fatigue. 3) We will determine the spatial and temporal associations between intracortical resorption and viable/nonviable osteocytes by combinin a roaches from the recedin studies.
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