Novel Molecules that Regulate Bone Formation and Bone Resorption

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.

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Basic Sciences

Year

2011

Author dc:creator

• Linares, Gabriel Robert

Contributors dc:contributor

• Mohan, Subburaman

• Medical Physiology
• Osteoporosis, Bone resorption; Bone formation
• Novel molecules
• Diabetes and Obesity Related Protein (DOR)
• Glutaredoxin 5 (Grx5)
• Claudin 18 (Cldn-18)

Statement dc: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.

Language dc:language

English

Repository record dc:identifier

https://scholarsrepository.llu.edu/etd/40

OAI identifier oai:identifier

oai:scholarsrepository.llu.edu:etd-1039