Targeting Piezo Ion Channels for Mitigation of Osteoarthritis Pain and Disease Progression
Abstract
Musculoskeletal disorders are common not only in Veterans and Service personnel but also in general populations. Osteoarthritis (OA), associated with joint injuries and aging, is a prevalent condition that causes significant health and social problems. The occurrence rate of OA in U.S. military personnel is up to 50% higher than in age-matched civilians, and knee injuries can result in total knee arthroplasty over the course of 15 years. OA occurs when the protective cartilage on the ends of bones wears down over time by mechanical stress. Trauma and aging are the most common causes of OA. OA causes two major clinical symptoms, functional impairment and pain. Unfortunately, there are currently no medical OA treatments that are effective in reducing pain, reducing cartilage damages, or slowing down OA progression. Pain in affected joints is sensed by sensory nerves. Tissue damage in OA increases secretion of pain-mediating molecules, including nerve growth factor (NGF), that act on pain-sensing nerves to increase their sensitivity to mechanical stimuli. This process, called “peripheral sensitization,” plays an important role in chronic, pathological pain in OA. These pain mediators have been targeted for treatment of OA pain. Clinical trials found that while blocking NGF was very effective in relieving pain in OA, it increased cartilage damage. Therefore, it is highly desired to identify therapeutic targets to effectively reduce pain in OA without negatively impacting OA disease progression. Mechanical stress activates ion channels expressed in sensory nerves and in other types of cells, including chondrocytes that form cartilage in the joint. Recently, it was demonstrated that peripheral sensitization by NGF requires the action of the recently discovered mechano-sensitive ion channel, Piezo2. Therefore, blocking Piezo2 can alleviate pain in OA. Piezo ion channels are also expressed in chondrocytes, and recent studies show blocking Piezo channels in chondrocytes protect them from death caused by mechanical insults. Based on these findings, we hypothesize that blocking Piezo channels reduces pain in sensory nerves and prevents disease progression in cartilage, and thus Piezo channels can be ideal therapeutic targets for OA. In this project, we propose to combine genetic models with reduced Piezo expression and surgically induced post-traumatic OA models to test this hypothesis. We will generate mice with sensory nerve-specific and cartilage-specific Piezo gene ablation upon OA induction in adult mice. Pain and OA will be evaluated by weight-bearing assay and histological analysis, respectively. At the conclusion of this project, we expect to gain insight into whether Piezo inhibition can be a novel treatment strategy mitigating both pain and disease in OA. Given that Piezo inhibitors have been already identified and safely used in animals, this project, if successful, will provide a strong basis for further translational research on Piezo-targeted therapy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910186
Entities
People
- Tatsuya Kobayashi
Organizations
- Massachusetts General Hospital
- United States Army