Controlling the Phenotype of Synovial Macrophages: A Novel Strategy to Modify the Pathogenesis and Symptoms of Post-Traumatic Osteoarthritis
Abstract
Topic Area: Post-traumatic Osteoarthritis Osteoarthritis (OA) is the leading cause of disability and medical discharge in military populations, occurring more frequently in active and former military personnel than the general population. One of the reasons OA occurs more frequently in military populations is a relatively high rate of traumatic joint injuries, such as a torn meniscus or anterior cruciate ligament (ACL). Even when surgical reconstructions are performed to repair meniscus or ACL tears, patients with history of joint trauma are still 10 times more likely to develop OA than uninjured individuals. In fact, nearly 75% of military personnel who underwent a knee replacement before the age of 50 reported a history of acute joint trauma. Notably, the onset of OA-related pain and disability due to “post-traumatic” OA (PTOA) occurs at a much younger age than most other cases of OA. As such, the effects of PTOA can be particularly devastating in military personnel, causing decades of OA-related pain and disability. So, what causes PTOA to develop after a joint injury? While not all traumatic joint injuries will progress to PTOA, those injuries that do progress appear to have higher levels of inflammation within the joint. This inflammation slowly degrades the joint cartilage, causes bone to remodel, and generates pain. Over years, the degeneration of the joint will compound and ultimately cause the joint to fail, resulting in the need for artificial implants to restore joint function. Prior to joint replacement, PTOA therapies largely focus on controlling joint inflammation through injection of corticosteroids or other anti-inflammatory drugs. Most current anti-inflammatory therapies focus on broadly suppressing inflammation throughout the joint, which offers temporary relief of PTOA symptoms, but generally does not prevent PTOA from progressing. To be clear, inflammation is a complex process, and temporary inflammation isn’t necessarily a bad thing. In fact, for tissues to repair themselves following injury, inflammation is necessary for wound healing. The difference in PTOA-affected joints is that the inflammation doesn’t resolve and becomes chronic. As such, joint tissues are perpetually generating signs of injury, and the immune system is persistently trying to clean up the injury, though unsuccessfully. This chronic cycle of “failed repair” causes continuous fragmentation of tissue, which incites inflammation from the immune system, which then causes further tissue fragmentation. The above anti-inflammatory strategies seek to break this cycle by broadly suppressing inflammation throughout the joint, including the cartilage, bone, and immune cells. However, as noted above, these broad anti-inflammatory strategies largely do not prevent PTOA from progressing. So, rather than control inflammation through broad anti-inflammatory agents, what if the immune system could be re-programmed, resetting the joint to a baseline inflammatory state and allowing joint tissues another chance to heal themselves? Natural mechanisms have evolved to regulate the immune system during wound healing and infection, including a pathway known as the CD200-CD200R inhibitory signaling pathway. When CD200 binds to CD200R on the surface of a cell, a powerful anti-inflammatory cascade is set off inside the cell, “re-programming” a pro-inflammatory cell to an anti-inflammatory state. Importantly, CD200R only exists on the surface of myeloid cells, a key cellular component of the immune system. As such, CD200 only directly affects the immune system, potentially allowing the cells in cartilage, bone, and other joint tissues an opportunity to repair the joint’s anatomy while the immune system is temporarily silenced. The discovery of the CD200-C200R inhibitory signaling pathway has created significant interest in manipulating the pathway as a therapy for multiple inflammatory diseases; however, to date, CD200 has neve
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810147
Entities
People
- Blanka Sharma
Organizations
- United States Army
- University of Florida