Dissertation/Thesis Abstract

Osteoprotegerin in Bone Biology: Investigation of Cellular Sources and Mechanisms of Regulation
by Cawley, Keisha Manva Marie, Ph.D., University of Arkansas for Medical Sciences, 2020, 101; 28000987
Abstract (Summary)

The secreted glycoprotein osteoprotegerin (OPG), which is encoded by the Tnfrsf11b gene, blocks the action of RANKL and is therefore a key factor that limits osteoclast differentiation and bone resorption. Mice and humans lacking OPG have markedly low bone mass, demonstrating the importance of this decoy receptor in normal bone homeostasis and pathophysiology. Although several different cell types have been proposed as sources of the OPG involved in the control of bone resorption, no studies have directly addressed this question. Therefore, we sought to identify the cell types that produce the OPG that controls bone resorption. Using a conditional allele for Tnfrsf11b, we found that osteoblasts produce the OPG that protects cancellous bone in growing and adult mice. In contrast, the cellular sources of OPG that protect cortical are more complex and include osteoblasts as well as other unknown cell types. Suppression of OPG production has also been implicated in the bone loss caused by glucocorticoid excess. Therefore, we attempted to identify the mechanisms by which glucocorticoids suppress Tnfrsf11b. We found that deletion of two different transcription factor binding sites that had been previously implicated in this process by others did not alter suppression of the gene by glucocorticoids. Nonetheless, we found that robust stimulation of Wnt/β-catenin signaling was able to prevent suppression of Tnfrsf11b by glucocorticoids, suggesting that this hormone may stimulate bone resorption by suppressing expression of one or more Wnt ligands.

Indexing (document details)
Advisor: O'Brien, Charles A.
Commitee: Almeida Schuller, Maria, Franco, Aime, Morello, Roy, Wight, Patricia
School: University of Arkansas for Medical Sciences
Department: Interdisciplinary Biomedical Sciences
School Location: United States -- Arkansas
Source: DAI-B 82/2(E), Dissertation Abstracts International
Subjects: Aging
Keywords: Bone, Osteoporosis, Osteoprotegerin, Remodeling, Resorption, Skeleton
Publication Number: 28000987
ISBN: 9798662568983
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