The Role of an Aggrecan 32mer Fragment in Post-Traumatic Osteoarthritis
Abstract
Our proposal specifically addresses the following 2015 Peer Reviewed Medical Research Program Priority Research Areas: (i) Post-traumatic osteoarthritis (PTOA): Development of preventative therapies and/or techniques to minimize the progression of PTOA after injury to the joint. (ii) Osteoarthritis (OA): Basic and translational research to identify treatments to reverse OA. Knee OA alone is estimated to affect ~250 million people worldwide. Acute knee injury is one of the most significant risk factors for the development of knee OA; 50%-70% of patients with anterior cruciate ligament (ACL) or meniscal injuries develop PTOA. In the United States, 200,000 ACL injuries occur each year. Knee injuries are 10 times more frequent in the military population compared with the general population. Indeed, OA and PTOA arising from acute injury including blast injury are the most prevalent reasons for personal to be declared unfit for active duty in the US military. Without effective treatment for the prevention of PTOA or management of clinical symptoms, and in particular pain, PTOA will remain a significant burden on military resources. We have published that a 32mer acid fragment of the cartilage molecule aggrecan has bioactivity that stimulates an inflammatory response in joint tissues via Toll-like receptor-2 (TLR-2). Recently, we made the unprecedented observation in a mouse model of PTOA that traumatic knee injury leads to increased unhealthy bone immediately below affected cartilage. This bone is dying (osteonecrotic) and lacks healthy cells, similar to human bone following acute joint injury. Our genetically modified mice (Chloe) have a mutation that blocks formation of the aggrecan 32mer. Remarkably, Chloe mice are protected from the osteonecrosis that is linked with regions of aggrecan loss in mouse models of PTOA, suggesting that the 32mer might mediate cartilage-bone crosstalk. In separate pain studies, we have discovered that the 32mer also activates nociceptors in cultures of knee-innervating dorsal root ganglia (DRG) (nerves). This effect is mediated through TLR2 expressed by nociceptors. We have further shown that 32mer-deficient Chloe mice fail to develop pain-related behaviors associated with experimental knee OA. Collectively, our data above suggest that blocking 32mer activity could have profound benefits for military personnel with joint injuries by protecting cartilage and bone against erosive joint damage and by blocking joint pain. Hypothesis: (1) The aggrecan 32mer contributes to the development and pathogenesis of PTOA. (2) Blocking aggrecan 32mer activity with monoclonal antibody AF-28 following joint injury will be cartilage-protective, bone-protective, and will provide effective pain suppression. Aim 1: Determine if and how therapeutic blockade of aggrecan 32mer can limit or prevents the severity of PTOA following acute knee injury. Aim 2: Develop a biomarker assay for detecting the 32mer in human synovial fluids and/or sera. This proposal combines our collective expertise in cartilage, bone, and pain biology in a "whole joint" approach to addressing the clinical impasse that is PTOA. Of course, this research opportunity carries the inherent risk that neutralizing the 32mer following joint injury might not prevent or reduce PTOA pathology or pain, but currently there are no alternative disease-modifying OA drugs (DMOADs) for the management of OA or PTOA. We predict that monoclonal antibody AF-28 targeting the 32mer peptide will neutralize 32mer activity in vivo. AF-28 binds to mouse and human 32mer with equal efficacy. If AF-28 can block 32mer activity, or, if the 32mer is identified as a biomarker for PTOA onset and progression, then this project will have been successful. Evidence of success will be identification of a translatable outcome that will impact the health, quality of life, and productivity of military personnel and to significantly decrease the incidence
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610706
Entities
People
- Amanda Fosang
Organizations
- United States Army
- University of Melbourne