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Novel Molecules that Regulate Bone Formation and Bone Resorption

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Title	Novel Molecules that Regulate Bone Formation and Bone Resorption
Author	Linares, Gabriel Robert
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.
Discipline	Physiology
Department	Basic Sciences
School	School of Medicine
Advisor	Mohan, Subburaman
Degree Name	Doctor of Philosophy
Degree Level	Ph.D.
Year Degree Awarded	2011
Date (Title Page)	June 2011
Language	English
Subject - LCSH	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
Copyright	Author
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.
Citation Information	To cite the digital version, include its Reference URL, found by following the link in the gray header above the digital file.
Collection	Loma Linda University Electronic Theses & Dissertations
Collection Website	http://archives.llu.edu/colls/lludis
Repository	Loma Linda University. Del E. Webb Memorial Library. University Archives

Title	Page 1
Full Text	LOMA LINDA UNIVERSITY School of Medicine in conjunction with the Faculty of Graduate Studies ____________________ Novel Molecules that Regulate Bone Formation and Bone Resorption by Gabriel Robert Linares ____________________ A Dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Physiology ____________________ June 2011

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