Abstract
Osteoarthritis (OA) is a joint disease that restricts motion and activity, increases risk for other health conditions, and costs the American economy billions of dollars every year. There are currently no disease-modifying treatments available; rather, treatment largely focuses on palliating patients and bridging them to joint replacement surgery. Our work has demonstrated the importance of epigenetic regulation and metabolic alterations in the pathogenesis of OA, specifically through a DNA methyltransferase 3B - 4-aminobutyric acid aminotransferase axis (DNMT3B-ABAT). We targeted this axis with RNA-peptide based nanoparticles and found that either part of the axis could be targeted to successfully mitigate OA pain and tissue changes in a murine injury model. In seeking to better understand the role ABAT plays in OA, we also found that this axis’ effects are partially mediated through the GABAB receptor in articular chondrocytes. This groundbreaking discovery both opens a new avenue for therapeutic investigation, and points to a definition of GABA not merely as a neurotransmitter, but as a small molecule metabolite that sits at the nexus of cellular energetics and cell signaling.
Committee Chair
Regis O'Keefe
Committee Members
Christine Pham; Farshid Guilak; Jie Shen; Marco Colonna
Degree
Doctor of Philosophy (PhD)
Author's Department
Biology & Biomedical Sciences (Molecular Cell Biology)
Document Type
Dissertation
Date of Award
3-13-2026
Language
English (en)
DOI
https://doi.org/10.7936/bgyy-jg98
Recommended Citation
Kucharski, Amir, "Targeting the DNMT3B-ABAT Axis in Osteoarthritis Using RNA-peptide Nanoparticles Reveals GABAB Signaling as a Critical Mediator of Articular Chondrocyte Homeostasis" (2026). Arts & Sciences Theses and Dissertations. 3725.
The definitive version is available at https://doi.org/10.7936/bgyy-jg98