The Role of Claudins in Bone Metabolism

<p>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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Basic Sciences

Year

2014

Author dc:creator

• Alshbool, Fatima Zakariya

Contributors dc:contributor

• Mohan, Subburaman
• Brantley, Eileen
• Buchholz, John N.
• Wright, Kenneth R.
• Zhang, Lubo

• Medicinal and Pharmaceutical Chemistry
• Medicine and Health Sciences
• Pharmacy and Pharmaceutical Sciences
• Bone and Bones - Metabolism; Calcification - Physiologic; Bone Density; Bone Resorption; Osteogenesis; Bone Morphogenetic Proteins; Claudins - Metabolism
• Osteoporosis; Bone Mass; Cldn-18; Cldn-1; Osteoblast Proliferation

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/222

OAI identifier oai:identifier

oai:scholarsrepository.llu.edu:etd-1221