Abstract

Osteoporosis is a disease characterized by decreased bone mass and microarchitectural deterioration of bone. Bone loss occurs when the increased bone resorption that occurs with age is not compensated by a corresponding increase in bone formation. Therefore, understanding the mechanisms which regulate bone formation and bone resorption is important for developing diagnostic and treatment strategies for osteoporosis. In my dissertation, we investigated the role of Glutaredoxin 5 (Grx5), Diabetes and Obesity Related protein (DOR), and Claudin 18 (Cldn-18), novel molecules involved in regulating bone formation and bone resorption. We demonstrated that Grx5 protects osteoblasts from oxidative stress induced apoptosis via a molecular pathway that involves regulation of reactive oxygen species production, cardiolipin oxidation, caspase activity, iron-sulfur cluster formation, and manganese superoxide dismutase activity. We found that DOR is an important regulator of osteoblast differentiation. In addition, a single nucleotide polymorphism (SNP) in the promoter of human DOR gene associated with plasma levels of the bone formation marker, osteocalcin, in men. Targeted disruption of the tight junction protein, Cldn-18, in mice led to significant deficits in peak bone mass due to increased bone resorption with no effect on bone formation. Cldn-18 is a novel negative regulator of osteoclast differentiation that interacts with ZO-2 to modulate RANKL signaling in osteoclasts. Collectively, these findings may provide insight into the molecular mechanisms which regulate bone formation and bone resorption, and may be useful in developing therapeutic strategies to prevent low bone mass.

LLU Discipline

Physiology

Department

Basic Sciences

School

School of Medicine

First Advisor

Mohan, Subburaman

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

January 2011

Date (Title Page)

6-1-2011

Language

English

Library of Congress/MESH Subject Headings

Osteoporosis, Bone resorption; Bone formation

Subject - Local

Novel molecules, Diabetes and Obesity Related Protein (DOR), Glutaredoxin 5 (Grx5), Claudin 18 (Cldn-18)

Type

Dissertation

Page Count

242 p.

Digital Format

Application/PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses & Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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