Honors Theses

Date of Award

2025

Document Type

Honors Thesis - NSU Access Only

Degree Type

Bachelors of Science

Degree Name

Biology

Department

Halmos College of Arts and Sciences and the Guy Harvey Oceanographic Research Center

Honors College

Farquhar Honors College Thesis

Honors College Dean

Andrea Nevins

Home College Dean

Robin Cooper

Faculty Advisor

Toshihisa Kawai

Faculty Advisor

Satoru Shindo

Abstract

Glucocorticoids (GCs), widely used for their anti-inflammatory effects, are a leading cause of glucocorticoid-induced osteoporosis (GIO). Recent findings by Hu et al. (2023) demonstrated that Yoda1, a chemical agonist of the mechanosensitive ion channel Piezo1, attenuates osteoporosis in ovariectomized mice, suggesting potential anti-resorptive effects. However, it remains unclear whether Yoda2—a Yoda1 derivative with stronger Piezo1 agonistic activity—can prevent GIO without triggering medication-related osteonecrosis of the jaw (MRONJ).

This study evaluates Yoda2's therapeutic potential in a mouse model of GIO, focusing on its effects on bone resorption and MRONJ.

GIO was induced in 3-week-old male C57BL/6 wild-type (WT), Piezo1flox/flox, and LysM-cre/Piezo1flox/flox mice (Piezo1LysMD ) mice via subcutaneous dexamethasone (Dex; 10 mg/kg, twice weekly for 4 weeks). Treatment groups received either Yoda2 (0.4 mg/kg, subcutaneous, twice weekly), Zoledronate (Zol; 250 µg/kg, subcutaneous, once weekly), or saline. To model MRONJ, 5-0 silk ligatures were placed to induce periodontitis, followed by the extraction of the left first and second molars. Bone morphometric parameters of the femur and alveolar bone were assessed using micro-CT, TRAP staining, and H&E staining. In vitro, bone marrow-derived mononuclear cells were cultured with M-CSF/RANKL ± Yoda2 (5 µM) and Dex (50 nM) for 7 days, followed by TRAP staining and pit formation assays.

In WT mice, Dex treatment led to significant reductions in bone mineral density (BMD) and deterioration of bone architecture—effects that were reversed by Yoda2 (P < 0.05). These protective effects were preserved in Piezo1flox/flox mice but absent in Piezo1LysMD mice (P < 0.01), indicating that Yoda2 acts through Piezo1 in myeloid-lineage cells. In vitro, Yoda2 significantly inhibited Dex-induced osteoclast formation and bone resorptive activity (P < 0.01). Notably, Yoda2 did not induce MRONJ following tooth extraction, in contrast to the Zol-treated group.

These findings suggest that Yoda2 protects against both systemic and periodontal bone loss by activating Piezo1 in osteoclasts, without promoting MRONJ, highlighting its therapeutic potential for managing GIO and associated complications.

Download
To access this thesis/dissertation you must have a valid nova.edu OR mynsu.nova.edu email address and create an account for NSUWorks.

Free My Thesis

If you are the author of this work and would like to grant permission to make it openly accessible to all, please click the Free My Thesis button.

Share

COinS