Use Immune System to Prevent, Treat OA After ACL Tears?

A $1.5 million grant from the Department of Defense (DoD) has been awarded to Kevin Baker, Ph.D., director of Orthopedic Research at Beaumont Health in southeast Michigan. The funds will be used to further research that could help slow the arthritis that occurs after an anterior cruciate ligament (ACL) injury—known as post-traumatic osteoarthritis (PTOA).

Dr. Baker told OTW, “Our group has been working in the area of ACL rupture-induced post-traumatic osteoarthritis (PTOA) for about five years. Data generated from an AOSSM [American Orthopaedic Society for Sports Medicine] New Investigator Research Grant on the subject in 2015, which focused on improving marrow-derived stem cell recruitment to the injured joint to slow ACL rupture-induced PTOA.”

“We then worked with Stewart Graham, Ph.D., director of Metabolomics at Beaumont Health, to characterize the systemic response to initial joint trauma and how that influenced the onset and progression of PTOA. High resolution mass spectrometry demonstrated that systemically, tryptophan metabolism was dysregulated in a manner similar to what is more commonly observed in patients with an inflammatory arthropathy like rheumatoid arthritis (RA) or systemic lupus erythematous (SLE).”

“This new grant combines our work in enhancing intra-articular recruitment of endogenous marrow-derived stem cell populations, with a particular focus on immunomodulating the microenvironment within the injured knee through alteration of tryptophan metabolism.”

“This metabolic pathway has proven to be extremely important in understanding how certain tumors are able to evade the immune system. We hypothesize that rebalancing tryptophan metabolism inside the knee joint will allow the stem cells that we have recruited to the knee to exert a more potent protective effect on articular cartilage and other tissues.”

“In our previous DoD grant, we observed that administering an FDA-approved drug that blocks a specific chemokine receptor directly after ACL rupture allows marrow-derived stem cells to be efficiently recruited inside the knee joint.”

“Without this chemokine receptor blockade, the endogenous marrow-derived stem cells that are mobilized into peripheral blood in response to the injury engraft in the synovium, which renders their ability to respond to injury ineffective.”

“We believe these cells play a primarily immunomodulatory role, and that further shifting the balance of tryptophan metabolism inside the knee joint will mitigate the onset of PTOA. During the grant, we will also be studying the efficacy of our combined treatment in established PTOA to determine if our treatment strategy can slow disease progression.”

“PTOA is the leading cause of disability in U.S. military personnel. The rate of PTOA in military personnel is more than double that of the civilian population and ACL rupture is amongst the leading injury mechanisms associated with development of PTOA in the knee.”

“There is a complex biologic cascade initiated immediately after ACL injury that we believe initiates joint destruction. Our aim is to disrupt this cascade using a combination of endogenous stem cells and an immunomodulatory approach which is able to be easily administered (subcutaneous injection) to patients in the very acute phase after injury.”

“Our approach to locally altering tryptophan metabolism centers on a single, intra-articular injection. This treatment approach could be utilized in challenging scenarios where advanced clinical/surgical facilities are out of reach. We want military personnel and civilians alike to recover quicker from joint trauma without the worry of needing a joint replacement at a young age.”

“We are grateful for the funding provided by the Peer-Reviewed Medical Research Program administered by the Congressionally-Directed Medical Research Program.”