Date of Award
Spring 5-10-2025
Level of Access Assigned by Author
Open-Access Thesis
Degree Name
Doctor of Philosophy (PhD)
Department
Biomedical Sciences
First Committee Advisor
Katherine Motyl
Second Committee Member
Karen Houseknecht
Third Committee Member
Clifford Rosen
Additional Committee Members
Derek Molliver
Christine Lary
Abstract
Bone is a dynamic tissue regulated by a variety of factors, including the nervous system. Adrenergic signaling regulates bone, classically thought to be mediated solely by osteoblasts. Here, we provide evidence for osteoclast-mediated mechanisms of adrenergic signaling via β2AR. To understand the role of osteoclast β2ARs, we created a mouse model deleting Adrb2, the gene encoding β2AR in osteoclasts. To test the hypothesis that osteoclast β2ARs are functional, we treated our osteoclast-specific knockout mice with salbutamol, a β2-selective agonist to determine if they were protected from salbutamol-induced bone loss. Male mice lacking osteoclast β2ARs did not experience bone loss in the vertebrae unlike their wildtype littermates.
Previous work identified deletion of Adrb2, in global and osteoblast-specific knockouts, leads to high bone density. We identified the effects of Adrb2 in bone depend on sex-, age-, and cell-type. Female mice were unaffected, but male mice exhibit low bone at 8 weeks of age, but not 12-26 weeks of age. This phenotype was caused by an increase in osteoclasts and reduction of osteoblasts. Further studies identified osteoclast conditioned media from our conditional knockout reduced osteoblast specific gene expression and Nlrc5. Together, these findings solidify that osteoclasts are also directly influenced by adrenergic signaling to regulate bone and that osteoclast β2AR influences osteoblasts through an altered secretome.
This work is translational to current investigation to repurpose β-blockers to prevent osteoporosis. Osteoporosis is a worldwide public health concern. Current osteoporosis treatments, while effective, can lead to rare, but severe side effects. An ongoing phase 2 clinical trial is testing the efficacy of atenolol, a β1-selective blocker, to prevent osteoporosis in postmenopausal women. Preclinical studies have utilized propranolol, a non-selective β-blocker to study effects on bone. Co-treatment with teriparatide (PTH) and propranolol, improves bone past that of either drug alone. Here, we tested if atenolol influenced bone in a mouse model, and if atenolol, like propranolol, further promoted the effects of PTH. Atenolol largely did not influence bone density alone or in combination with PTH. These findings highlight the importance of utilizing human samples to understand the effects of atenolol and mechanisms altered throughout atenolol administration.
Recommended Citation
Fontaine, Rebecca, "The Functional Role of β2-Adrenergic Receptor in Osteoclasts" (2025). Electronic Theses and Dissertations. 4151.
https://digitalcommons.library.umaine.edu/etd/4151