Here we highlight exciting topics and scientists from the field of comparative medicine to foster translational science.

Role of the Immune System in Post-Traumatic Osteoarthritis
Progression in a Naturally Occurring Equine Model
Brought to you by Lynn Pezzanite, DVM, MS, PhD, Diplomate ACVS-LA

Osteoarthritis (OA) is a progressive, degenerative condition that affects over 550 million people worldwide. Human patients with post-traumatic osteoarthritis (PTOA) have low-grade infiltration of immune cells including macrophages and T cells in the synovial fluid and synovium of affected joints.1 In mouse models of PTOA, T cells such as pro-inflammatory T Helper 17 (Th17) cells infiltrate the joint within one week after anterior cruciate ligament transection.2 In the destabilization of the medial meniscus model, immunosuppressive regulatory T cells (Treg) are detected in the joint within one month of injury.3 Th17 cells release pro-inflammatory and catabolic cytokines including IL-17A while Tregs suppress immune responses and inflammation through secretion of anti-inflammatory cytokines such as IL-10 and TGB-β.4,5

Taken together, these studies suggest that a Treg:Th17 imbalance could contribute to PTOA progression and joint destruction. Naturally occurring equine PTOA presents greater similarities to the human condition in temporal progression of disease, joint volume, cartilage thickness and articular cartilage loading forces compared to other species and therefore represents a valuable animal model to further elucidate the mechanisms contributing to Treg:Th17 imbalance.

In recent studies supported by NIH R01 AR071394 and the Paula Kennedy-Harrigan fund, Dr. Lisa Fortier, DVM, PhD and collaborators at Cornell University, investigated Treg:Th17 imbalance in early PTOA.6 Synovial fluid and peripheral blood samples were collected from horses with naturally occurring PTOA undergoing arthroscopy and compared to normal joints to test the hypothesis that a dynamic Treg:Th17 imbalance is present in PTOA providing future opportunities for immunomodulatory therapy. Joints were classified as mild or moderate posttraumatic osteoarthritis. Synovial fluid and blood cells were analyzed by flow cytometry and synovial fluid was analyzed by enzyme-linked immunosorbent assay. On analysis, CD3+ T cells represented the majority (81%) of lymphocytes in synovial fluid which increased in moderate PTOA. Additionally, CD14+ macrophages were doubled in moderate vs. mild PTOA and controls. T Helper 17 cells and Th-17-like Regulatory T cells were increased in moderate PTOA compared to mild or non-operated joints.

This work suggests that that regulatory T cell: T Helper 17 cell imbalance and increased levels of T Helper 17 cell-like Regulatory T cells are associated with more severe PTOA disease processes. These findings provide novel insights into immunological mechanisms of progression and pathogenesis and support the concept that early and targeted use of immunotherapeutics may mitigate PTOA may improve clinical outcomes.

1 de Lange-Brokaar BJE, Ioan-Facsinay A, van Osch GJVM, et al. Synovial inflammation, immune cells and their cytokines in osteoarthritis: A review. Osteoarthritis Cartilage. 2012;20(12):1484–1499.

2 Faust HJ, Zhang H, Han J, et al. IL-17 and immunologically induced senescence regulate response to injury in osteoarthritis. Journal of Clinical Investigation. 2020;130(10):5493–5507.

3 Haubruck P, Colbath AC, Liu Y, Stoner S, Shu C, Little CB. Flow cytometry analysis of immune cell subsets within the murine spleen, bone marrow, lymph nodes and synovial tissue in an osteoarthritis model. Journal of Visualized Experiments. 2020;2020(158).

4 Sandquist I, Kolls J. Update on regulation and effector functions of Th17 cells. F1000Res. 2018;7(205):1–8.

5 Shevyrev D, Tereshchenko V. Treg Heterogeneity, Function, and Homeostasis. Front Immunol. 2020;10.

6 Keller LE, Tait Wojno ED, Begum L, Fortier LA. T Helper 17-like Regulatory T cells in equine synovial fluid are associated with disease severity of naturally occurring posttraumatic osteoarthritis. Am J Sports Med. 2023;1047-1058. Doi: 10.1177/0363523115388.