Since blood vessels play an important role during bone remodeling, certain aspects of bone disease may be attributable to dysfunction of bone blood vessels. Data in this proposal suggest that bone blood vessels in aged animals may be spatially distant from bone. Thus, age-related osteoporosis may be partially derived by an increased spatial distance of bone blood vessels from bone forming sites, reducing blood flow and nutrient exchange. We previously demonstrated that intermittent parathyroid hormone (PTH) administration, a common treatment for osteoporosis, brings bone blood vessels closer to sites of bone formation, theoretically creating a microenvironment favorable for bone accrual. This phenomenon occurred independent of the creation of new blood vessels. Further, intermittent PTH administration augmented the expression of matrix metalloproteinase- 9 (MMP-9) by cells of bone and bone marrow. Matrix metalloproteinase-9 causes matrix degradation and has the capacity to mobilize progenitor cells from the bone marrow, contributing to cellular migration. Thus, in lieu of eliciting cellular migration, it is hypothesized that enhanced expression of MMP-9 with intermittent PTH administration will mechanistically permit the spatial redistribution of bone blood vessels toward bone forming sites. While intermittent PTH administration alters the spatial location of bone blood vessels, this phenomenon may occur under varying physiological conditions. Thus, in addition to elucidating the mechanisms associated with bone blood vessel relocation, this proposal will also investigate the effects of other stimuli (i.e., advanced age and mechanical loading) on the spatial redistribution of bone blood vessels. The purposes of this investigation are to determine 1) whether bone blood vessel distance from active bone forming sites is augmented as a function of age, 2) whether these distances are reversed with intermittent PTH administration, 3) whether this phenomenon occurs independent of the creation of new bone blood vessels, 4) whether bone blood vessel relocation is related to MMP-9 activity and 5) whether stimuli other than PTH (i.e., mechanical loading) elicits bone blood vessel redistribution. Analyses will be made among young (4-6 mon) and old (22-24 mon) male Fischer-344 rats exposed to 15 days of intermittent PTH administration or a placebo (Specific Aim1) or exposed to 3 days of mechanical loading of the ulna (Specific Aim 2). Micro-CT, bone histomorphometry and immunolabeling will be utilized to assess bone microarchitecture, bone static and dynamic properties, bone vascular density and the distance between bone blood vessels and sites of new bone formation. In addition, to determine whether PTH stimulates the creation of new bone blood vessels, in vitro cell culture experiments will be conducted on bone marrow endothelial cells to detect the presence of endothelial tube formation (Specific Aim 3). Findings will provide novel information concerning bone blood vessels location as a function of age, intermittent PTH administration and mechanical loading and determine whether bone blood vessel relocation is related to MMP-9 activity.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM113125-03
Application #
9432531
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Delaware
Department
Type
DUNS #
059007500
City
Newark
State
DE
Country
United States
Zip Code
19716
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