Abstract

Osteoporosis, a major public health problem in the U.S., is characterized by low bone mass and structural deterioration of bone tissue. Since the imbalance between bone formation and bone resorption during bone remodeling has been documented to be a major factor in the pathogenesis of osteoporosis, it is crucial to identify novel genes and/or novel functions of known genes that regulate the formation and activity of bone forming osteoblasts and bone resorbing osteoclasts. To this end, recent evidence suggests a significant role for caudins (Cldns), which comprise a major group of tight junction proteins, in bone biology and development. This notion is based on our previous studies which demonstrated that Cldn-18 knockout (KO) mice developed osteopenia phenotype by increasing bone resorption and osteoclast differentiation. Since Cldn-18 is known to be predominately expressed in the stomach, and it was globally disrupted in these earlier studies, in this dissertation we tested the possibility that the osteopenia phenotype in these mice is due to its disruption in the stomach. We found that loss of Cldn-18 reduced gastric acidity and serum calcium in adult mice. However, correction of serum calcium deficit did not rescue the osteopenia phenotype observed in Cldn-18 KO mice, thus suggesting that increased bone resorption is likely to be due to direct effects of lack of Cldn-18 on osteoclasts, and not due to gastric pH changes caused by its loss in the stomach. Since the Cldn family consists of 27 members, in a separate set of studies, their expression was examined during osteoblast and osteoclast differentiation. We found that several Cldns are expressed in bone, in a complex, cell type and differentiation stage-dependent fashion. Moreover, of those Cldns found to be expressed, a key member, namely Cldn-1, was found to be a positive regulator of osteoblast proliferation and differentiation, and is regulated by several osteoregulatory factors. Collectively, our studies suggest that Cldns play important non canonical functions in regulating bone cell signaling, and may lay down the foundation for the development of Cldn-based agents for diagnosis and therapeutic management of osteoporosis.

LLU Discipline

Pharmacology

Department

Basic Sciences

School

School of Medicine

First Advisor

Mohan, Subburaman

Second Advisor

Brantley, Eileen

Third Advisor

Buchholz, John N.

Fourth Advisor

Wright, Kenneth R.

Fifth Advisor

Zhang, Lubo

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2014

Date (Title Page)

12-2014

Language

English

Library of Congress/MESH Subject Headings

Bone and Bones - Metabolism; Calcification - Physiologic; Bone Density; Bone Resorption; Osteogenesis; Bone Morphogenetic Proteins; Claudins - Metabolism

Subject - Local

Osteoporosis; Bone Mass; Cldn-18; Cldn-1; Osteoblast Proliferation

Type

Dissertation

Page Count

175

Digital Format

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 and Dissertations

Collection Website

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

Repository

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

Download

Share

COinS