| Author: | Liu, Jun |
| Title: | Chondrocytic acetylcholinesterase/alpha7 nAChR signaling in cartilage homeostasis and osteoarthritis |
| Advisors: | Wen, Chunyi (BME) |
| Degree: | Ph.D. |
| Year: | 2026 |
| Department: | Department of Biomedical Engineering |
| Pages: | xviii, 97 pages : color illustrations |
| Language: | English |
| Abstract: | Background Emerging evidence indicates a bidirectional link between neurodegenerative and skeletal disorders, positioning osteoarthritis (OA) within a systemic "brain–joint axis" regulated by cholinergic signaling. Central to this axis, dysregulation of acetylcholinesterase (AChE), acetylcholine (ACh) and the α7 nicotinic acetylcholine receptor (α7nAChR) perturbs cholinergic homeostasis and promotes inflammation and tissue catabolism. We hypothesized that AChE/ACh/α7nAChR dysregulation in bone and cartilage accelerates OA progression by disrupting cholinergic signaling, and that targeting AChE/ACh/α7nAChR signaling restores joint protection. We aimed to define cholinergic signaling in cartilage homeostasis and OA, test the chondroprotective effects of AChE modulation in vitro and in vivo, and delineate mechanisms involving ACh and α7nAChR mediated anti-inflammatory pathways. Hypothesis We hypothesized that dysregulated AChE/ACh/α7nAChR signaling in joint tissues promotes OA progression by disrupting cholinergic homeostasis, and that targeting AChE would restore ACh/α7nAChR mediated joint protection. Objectives This study aims to elucidate cholinergic signaling in cartilage homeostasis and OA, determine the chondroprotective effects of AChE modulation in vitro and in vivo, and clarify its mechanisms via ACh/α7nAChR mediated anti-inflammatory pathways. Key Findings Analysis of public RNA-sequencing datasets implicated the involvement of cholinergic signaling, and inflammatory cascades in OA pathogenesis. OA cartilage showed increased expression of cholinergic components (e.g., CHRNA7, CHRNA10 and COLQ) and inflammatory mediators (e.g., MMP-13 and TNFAIP1), underscoring pathway dysregulation in disease. In vitro, siRNA knockdown of AChE in IL-1β stimulated chondrocytes reduced inflammatory cytokines, including TNF-α and IL-6. In vivo, genetic AChE deletion in chondrocytes or osteoblasts mitigated cartilage deterioration, synovial degeneration, preserved subchondral bone, and improved pain-related or locomotor outcomes after surgically induced OA, accompanied by lower AChE, Nf-kB, and TNF-α expression. In a collagenase induced inflammatory OA model, chondrocyte-specific AChE deletion similarly reduced subchondral bone loss. Pharmacological treatment with AChE inhibitor donepezil decreased inflammatory cytokine TNF-α expression and increased ACh at serum level, which attenuated cartilage degeneration, synovial inflammation and subchondral bone loss in a hypertensive rat OA model. Mechanistically, immunofluorescence demonstrated co-localization of AChE and α7nAChR in human OA chondrocytes and cartilage, suggesting functional proximity. Functional assays indicated that AChE inhibition exerts anti-inflammatory effects via α7nAChR activation and the cholinergic anti-inflammatory pathway; under inflammatory conditions, an α7nAChR antagonist (α-bungarotoxin) reversed these effects. Ion channel imaging indicated both ACh-treated and AChE-knockdown chondrocytes displayed increased ion channel activation relative to untreated cells. Electrophysiological recordings further supported that AChE knockdown can partially counteract the inhibitory effects of α7nAChR antagonism on cholinergic signaling. Conclusion This thesis demonstrates AChE contributes to OA pathogenesis by modulating joint inflammation and cartilage degradation. Genetic and pharmacological AChE inhibition confer chondroprotection across models, with effects mediated through AChE/ACh/α7nAChR signaling and local cholinergic anti-inflammation pathways. The AChE/α7nAChR axis therefore represents a promising therapeutic target for disease modification in OA. |
| Rights: | All rights reserved |
| Access: | open access |
Copyright Undertaking
As a bona fide Library user, I declare that:
- I will abide by the rules and legal ordinances governing copyright regarding the use of the Database.
- I will use the Database for the purpose of my research or private study only and not for circulation or further reproduction or any other purpose.
- I agree to indemnify and hold the University harmless from and against any loss, damage, cost, liability or expenses arising from copyright infringement or unauthorized usage.
By downloading any item(s) listed above, you acknowledge that you have read and understood the copyright undertaking as stated above, and agree to be bound by all of its terms.
Please use this identifier to cite or link to this item:
https://theses.lib.polyu.edu.hk/handle/200/14609