Targeting Proton-Activated Chloride Channel PACc for Treating Osteoarthritis Pain
Abstract
Osteoarthritis is the most common form of arthritis, affecting millions of people worldwide, particularly the military personnel who are subjected to extreme physical demand and frequently get injured in the battlefield. It occurs when the protective cartilage on the ends of the bones (subchondral bone) wears down over time. Joint pain is the primary symptom of osteoarthritis and profoundly affects the quality of life of osteoarthritis patients. Unfortunately, current arthritis pain managements are limited to nonsteroidal anti-inflammatory drugs or general pain killers. These drugs have limited effect in controlling arthritis pain while long-term use results in severe side effects such as opioid addiction. Thus, it is imperative to seek new therapeutic strategy to manage osteoarthritis pain. Subchondral bone is enriched with pain sensory nerve fibers and has been identified as one of primary source of joint pain. We found that the sensitivity of the nerve fibers in the subchondral bone is significantly increased during arthritis progression, but the causes of this phenomenon are still not known. We believe unveiling the mechanism of increased neuronal sensitivity in the osteoarthritic subchonral bone will lead to discovery of novel treatment for osteoarthritis pain. Our pilot experiments indicate that the activity of osteoclasts are responsible for the destruction of subchondral bone and joint pain. The osteoclasts are a group of bone resorption cells. During the process of bone resorption, these cells release protons to digest the minerals of the bony tissue. In the osteoarthritic subchondral bone, the activity of osteoclast is significantly elevated. As a result, there is a large amount of protons released by the osteoclasts, which makes the local environment become acidic while acidosis is a known noxious chemical stimulus that induces pain. We are therefore aiming to investigate whether and how overactivation of osteoclast-induced acidosis in subchondral bone leads to joint pain. We have identified a novel chloride channel, named as proton-activated-chloride channel (PAC) in the previous study. The PAC possess a unique characteristic that only can be active in an acidic environment. The purpose of this study is to determine whether the activation of PAC in never fibers results in excitation of the neurons and increased pain signals to be sent to the brain and whether blocking PAC can effectively inhibit joint pain in osteoarthritis patients. Since there is a lack of an effective drug on the market for osteoarthritis pain, the success of the work described in this proposal will facilitate and accelerate therapeutic development of this disease and reduce the risk of opioid addiction.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110045
Entities
People
- Gehua Zhen
Organizations
- Johns Hopkins University
- United States Army