The Role of Mitochondrial Damage Associated Molecular Patterns (mDAMPs) in Equine Joint Injury and Disease
Principal Investigator: Michelle Delco
DESCRIPTION (provided by applicant):
The broad objective is to investigate the role of mitochondrial Damage-Associated Molecular Patterns (mDAMPs) in traumatic joint injury and the development of osteoarthritis (OA) in the horse.
In many tissues, mDAMPs are known to be released after injury by cells undergoing mitochondrial dysfunction, and act to perpetuate inflammation and tissue damage. We have
recently demonstrated that mitochondrial dysfunction is one of the first pathologic responses of chondrocytes to cartilage injury, and importantly, that mitoprotective therapy prevents injuryinduced cell death and cartilage degeneration. However, the basic mechanisms whereby mitochondrial dysfunction leads to posttraumatic osteoarthritis (PTOA) are not well understood. Our preliminary data and findings from Year 1 of this study provide the first evidence that chondrocytes release mDAMPs in response to cellular stress and more specifically, mitochondrial dysfunction.
To test the hypothesis that mDAMPs are released from chondrocytes in response to cartilage trauma, and that these extracellular damage signals are associated with clinical joint trauma, we will measure the levels of extracellular mDAMPs in several model systems. First, to better understand the signals that trigger mDAMP release, we will stress chondrocytes in vitro with compounds known to initiate mDAMP release in other cell types. Next, we will determine if mechanical injury to cartilage initiates mDAMP release ex vivo. To determine if impact injury to the articular surface results in mDAMP release in vivo, mDAMP concentration will be measured in banked joint fluid from horses that had experimental joint trauma. Finally, to determine if mDAMP release is associated with naturally-occurring joint injury, and if mDAMP levels in joint fluid may be a useful indicator of early joint trauma, mDAMPs will be measured in horses presenting to the hospital for treatment of joint injury.
Understanding the role of mDAMPs has the potential to change the way we diagnose and treat joint injury in horses. Currently available therapies only mask pain, and are instituted after irreversible cartilage and bone damage have already occurred, predispoing horses to further injury. The ultimate goal of this research is to develop targeted disease-modifying therapies to\ break the cycle of ongoing damage. Furthermore, mDAMPs are promising candidate biomarkers, and screening in joint fluid could serve as a practical test for early joint damage, to identify horses requiring early therapy or modified training programs. This work will provide an important foundation for future studies, and data necessary to compete for larger extramural grants.