Butti, Clarissa;
(2024)
Mechanisms and treatment of osteoarthritis pain.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Osteoarthritis (OA) is the most common, highly debilitating form of arthritis which still lacks resolutive treatments in the clinic. This project, comprised of two major parts, describes new approaches to study and treat OA pain. In the first part (Chapter 2), we aimed to reproduce a Mechanical Joint Loading (MJL) model of OA with a new version (ElectroForce 3200) of a bone-loading machine. We trialed and optimized multiple loading regimes on wild-type mice. Initially, we selected the 11 N 3 times/week for 2 weeks loading regime, as the loaded group showed a mild ipsilateral mechanical hypersensitivity. The selected regime, tested a second time, failed to induce a pain behaviour, even if µCT scans showed clear OA signs in the loaded knee joints. We therefore hypothesized that the displacement force was the key parameter to modify. By applying a higher displacement in a 9 N 3 times/week for 2 weeks loading regime, the loaded mice showed a significant mechanical hypersensitivity, evaluated by behavioural tests, which was confirmed at the cellular level by GCaMP imaging. The second part describes potential new strategies to treat OA pain. Chapter 3 shows the efficacy of the chemogenetic receptor PSAM4-GlyR in obtaining pain relief in a model of inflammatory pain. Furthermore, the PSAM4-GlyR was proven an exceptional analgesic tool in different models of acute and chronic pain. In Chapter 4 we explored the possibility of inhibiting the Nav1.8 channel by blocking its interaction with p11, a protein crucial for its function. By using surface plasmon resonance, we identified two potential blockers (A2ti-1 and JW2-13) of the p11-NaV1.8 complex. Future directions involve the testing of both strategies investigated in this thesis (the PSAM4-GlyR chemogenetic tool and the p11-Nav1.8 blocking) in the MJL model for the treatment of OA pain.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Mechanisms and treatment of osteoarthritis pain |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2024. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10192019 |
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