Seungyong Lee

ORCID Identifier(s)

0000-0002-5397-6889

Graduation Semester and Year

2018

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Kinesiology

Department

Kinesiology

First Advisor

Rhonda D Prisby

Abstract

Advancing age is associated with progressive bone loss, declines in vasodilator capacity of blood vessels, vascular rarefaction and bone marrow blood vessel ossification. Intermittent parathyroid hormone (PTH) administration augments bone volume and is an anabolic agent used to treat osteoporosis in a duration-dependent manner. In animal research, at least 15 days of intermittent PTH administration is required to achieve bone accrual. However, physiological stimuli such as intermittent PTH administration effects the bone vascular system more rapidly; i.e., changes in the bone vascular system precede alterations in bone. Intermittent PTH administration also increases vasodilator capacity of bone blood vessels; however, data regarding its influence on bone blood flow and angiogenesis are variable. Further, intermittent PTH administration relocated bone marrow blood vessels closer to sites of bone formation, presumably directing blood flow to areas of high metabolism. A potential mechanism by which this may occur is via the secretion of matrix metalloproteinase (MMP)-9, which participates in extracellular matrix remodeling, the migration and homing of cells, and angiogenesis. In contrast, intermittent PTH administration may have unaddressed negative consequences. Bone marrow blood vessel ossification is the progressive conversion of blood vessels into bone with advancing age. Given its role in bone formation, intermittent PTH administration may exacerbate this pathology. Thus, I sought to quantify ossified bone marrow blood vessels, bone vascular density, the distance between trabecular bone surfaces and bone blood vessels, and the role of MMP-9 in relation to age (Mature vs. Middle-Aged) and short-term (5- and 10-days) intermittent PTH 1-34 administration. The animal ages selected in this dissertation coincide with the initiation of bone loss and bone vascular impairment across the life span. Also, the short duration of intermittent PTH 1-34 administration allows for the assessment of vascular changes prior to the changes in bone. Specific Aim 1 assessed the influence of short-term (5- and 10-days) intermittent PTH 1-34 administration on bone and bone marrow blood vessel ossification in Mature (6-8mon; n=30) and Middle-Aged (10-12mon; n=30) male and female C57BL/6 mice. Bone parameters were unaltered; however, ossified vessel volume tended (p=0.057) to increase and ossified vessels were 44% thicker (p<0.05) in Middle-Aged vs. Mature mice. Additionally, ossified vessels tended (p=0.08) to be 41% thicker following 10 days of PTH treatment. Specific Aims 2 and 3 assessed the influence of short-term intermittent PTH 1-34 administration on bone microarchitecture and bone static and dynamic properties, bone vascular density, the distance of bone marrow blood vessels (1-29 ?m, 30-100?m and 101-200?m in diameter) from trabecular bone, and MMP-9 density, area and localization in relation to trabecular bone and bone marrow blood vessels. Mature (n=60) and Middle-Aged (n=60) male and female C57BL/6 mice received PTH 1-34 or a vehicle for 5- and 10-days consecutive days. The number of small (1-29µm) bone marrow blood vessels was increased (p<0.05) by day 10, coinciding with augmented (p<0.05) MMP-9 density closest (p<0.05) to these smaller (1-29µm) blood vessels. The overall effects of intermittent PTH administration on the bone vascular system are positive. However, the data reveal a troubling tendency in regards to bone marrow blood vessel ossification, which may ultimately impact blood flow delivery to bone with advancing age.

Keywords

Parathyroid Hormone, Bone Vascular Alterations, MMP-9

Disciplines

Kinesiology | Life Sciences

Comments

Degree granted by The University of Texas at Arlington

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