Author ORCID Identifier
https://orcid.org/0000-0001-5673-6234
Defense Date
2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Biomedical Engineering
First Advisor
Henry J Donahue, Ph.D.
Second Advisor
Jennifer L. Puetzer, Ph.D.
Third Advisor
Michael J. McClure, Ph.D.
Fourth Advisor
Jolene J. Windle, Ph.D.
Fifth Advisor
Charles R. Farber, Ph.D.
Abstract
Bone loss is frequently experienced by individuals undergoing long-term disuse, such as prolonged bedrest, immobilization due to paralysis or injury, and conditions such as spaceflight. Under normal physiological conditions, bone remodeling is balanced by bone-forming osteoblasts and bone-resorbing osteoclasts, and the activity of osteoblasts and osteoclasts is orchestrated by osteocytes. Osteocytes are the most abundant cell type found in bone and ample evidence suggests they are bone’s main mechanosensory cell type. Therefore, understanding osteocyte biology and responses to mechanical signals, or lack thereof during unloading, may lead to new therapeutic targets to combat bone loss during disuse. Previous data has shown that connexin 43 (Cx43), the predominant gap junction protein in bone, plays a significant role in unloading-induced bone loss. We have shown that loss of Cx43 in osteoblasts and osteocytes mitigates the catabolic effects of unloading-induced bone loss, however, the mechanism by which this occurs, and whether it is osteocyte-specific, is not known.
We investigated the hypothesis that osteocyte-specific Cx43 deficiency increases bone remodeling and osteopenia and attenuates unloading-induced bone loss via a mechanism involving WNT/b-catenin and RANKL/OPG signaling pathways. We utilized both in vitro and in vivo models to characterize osteocytic Cx43 deficiency and in vivo models to examine the mechanism by which deficiency of Cx43 attenuates unloading-induced bone loss. We also utilized an osteocyte-specific Cx43 and b-catenin deficient in vivo model to examine the interaction of Cx43 and b-catenin and its role in unloading-induced bone loss. Identifying specific Cx43-related pathways that can explain bone adaptation to its mechanical environment has the potential to uncover novel therapeutic targets to help prevent disuse-induced bone loss.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-8-2024
Included in
Biomechanics and Biotransport Commons, Molecular, Cellular, and Tissue Engineering Commons