Abstract
Osteoarthritis (OA) is a complex disease involving mechanical and inflammatory factors that affect both the joint and systemic environments. Despite its prevalence as a leading cause of pain and disability worldwide, no disease-modifying OA drugs (DMOADs) are currently available. This dissertation focuses on exploring key targets and developing innovative tools to combat OA, addressing its mechanical and inflammatory drivers both independently and in combination. First, we investigated the role of mechanosensitive ion channels Piezo1 and Piezo2 in OA pathogenesis using a murine destabilization of the medial meniscus (DMM) model. Our findings demonstrated that knocking out Piezo1, Piezo2, or both in chondrocytes had significant effects on cartilage integrity, synovial inflammation, and pain. A Piezo1 knockout suggests a potential delay in disease onset, as indicated by pain and behavior data, but ultimately led to severe cartilage damage and heightened synovitis. Meanwhile, a Piezo2 KO showed a sex-specific effect, exacerbating cartilage damage in female mice but reducing pain-related behaviors. Notably, a dual Piezo1 and Piezo2 knockout provided a protective phenotype in male and female mice, reducing cartilage damage, synovial inflammation, and pain, underscoring the compensatory and synergistic roles of these channels in OA progression. Next, we explored the intersection of obesity-induced inflammation and mechanical injury in OA progression. Using a murine model combining DMM surgery and a high-fat diet (HFD), we investigated the role of the mechanosensitive ion channel Piezo1 in obesity-associated OA. Obesity induces a chronic pro-inflammatory state, characterized by elevated levels of adipokines such as IL-6, IL-1α, and leptin, which exacerbate cartilage degradation and amplify mechanical stress responses in chondrocytes. Preliminary findings revealed sex-specific roles for Piezo1 in cartilage protection and pain progression. A Piezo1 knockout reduced inflammation and altered pain behaviors in male and female mice and reduced cartilage damage in female mice, highlighting its critical role in driving the mechanoresponse of chondrocytes in obesity-associated OA. These results emphasize the combined impact of systemic inflammation and abnormal joint loading in OA pathogenesis and suggest that targeting Piezo1 holds promise as a therapeutic strategy to mitigate both structural and symptomatic aspects of OA, particularly in patients with obesity. To further dissect the impact of obesity-induced inflammation on cartilage health, we investigated the interplay between systemic inflammatory mediators and chondrocyte mechanotransduction in a murine diet-induced obesity (DIO) model. By examining both the pericellular matrix (PCM) and extracellular matrix (ECM) of knee cartilage, alongside isolated chondrocytes subjected to adipokines and inflammatory cytokines, we explored the dual influence of metabolic and mechanical factors on cartilage degeneration. While no significant differences in PCM or ECM mechanical properties were observed between HFD-fed and chow-fed mice, the pronounced effects of IL-6 and TNF-α on chondrocyte deformation and calcium signaling highlighted the critical role of systemic inflammation in early cartilage changes. Piezo1 inhibition attenuated these inflammatory effects, emphasizing its role in mediating mechanotransduction under pro-inflammatory conditions. These findings underscore the importance of systemic inflammation in obesity-associated OA and suggest that Piezo1 inhibition could serve as a promising therapeutic strategy to preserve cartilage health in inflammatory environments. Finally, we developed a novel platform for studying adipokine signaling in OA progression. Using genome-edited murine induced pluripotent stem cells (iPSCs), we created genetically engineered adipocytes capable of adipogenic differentiation and in vivo engraftment. These engineered cells allow for precise manipulation of adipokine secretion, enabling the study of adipose-derived signaling in OA and other conditions. Transplantation of these adipocytes into fat-free lipodystrophic mice challenged with DMM surgery provides a robust model to disentangle the roles of individual adipokines in OA progression and test therapeutic strategies. This work advances the field of OA research by identifying Piezo ion channels as critical mediators of mechanotransduction and inflammation in OA, highlighting their potential as therapeutic targets. The integration of diet-induced obesity and joint injury models provides novel insights into the synergistic effects of systemic inflammation and mechanical stress on cartilage health. Additionally, the development of genetically engineered adipocytes offers a transformative tool for studying adipokine signaling and exploring adipose tissue as a therapeutic target. Collectively, this research underscores the multifaceted nature of OA and provides a robust foundation for advancing the development of novel disease-modifying therapies.
Degree
Doctor of Philosophy (PhD)
Author's Department
Biomedical Engineering
Document Type
Dissertation
Date of Award
5-9-2025
Language
English (en)
DOI
https://doi.org/10.7936/j693-ra92
Recommended Citation
Ely, Erica Valentine, "Osteoarthritis as a Multi-Factorial Disease: Exploring Piezo Ion Channels and Adipose Tissue as Therapeutic Targets" (2025). McKelvey School of Engineering Theses & Dissertations. 1247.
The definitive version is available at https://doi.org/10.7936/j693-ra92