Babak Moradi, M.T. Jackson, Cindy C. Shu, Susan M. Smith, Margaret M. Smith, S. Zaki, Hadrian Platzer, Nils Rosshirt, David Giangreco, Carla R Scanzello, Christopher B. Little
Objective Identification of osteoarthritis (OA)–specific synovial inflammatory pathways and their temporal relevance is critical for therapeutic targeting. We compared mononuclear inflammatory/immune cell responses following joint injury that does or does not lead to OA to define bona fide OA‐associated cellular events. Methods We undertook detailed temporal flow cytometric and messenger RNA (mRNA) expression analysis in mice after sham or destabilization of the medial meniscus (DMM) surgery. This was compared with patients with meniscal injury and OA, evaluating the role of synovial monocytes/macrophages versus lymphocytes in catabolic metalloproteinase secretion in vitro. We determined the effect of transient or delayed systemic T cell depletion on DMM‐induced OA pathology. Results OA‐inducing/DMM and non–OA‐inducing/sham surgery had an identical synovial monocyte/macrophage number, activation, and polarization. The number and activation of synovial (not splenic or peripheral blood) CD4 + and CD8 + lymphocytes were increased from one day after DMM versus sham and showed a persistent cyclical elevation throughout OA onset and progression. There was a temporal imbalance in synovial Th17/Treg and Th1/Th2 lymphocytes during DMM‐induced OA initiation and progression. We confirmed early postinjury and late OA CD3/CD8 T cell responses in synovial tissues from patients, identified an association between CD8 and early postinjury symptoms, and defined a significant role for CD3 + T cells in synovial metalloproteinase secretion. Anti‐CD3 cell depletion studies in mice provided an initial approach to testing this hypothesis, offering preliminary evidence that early postinjury T cell responses may be associated with long‐term OA pathology. Conclusion We identify a hitherto unappreciated pathophysiologic role of acute T cell activation after joint injury in long‐term posttraumatic OA risk, providing a novel diagnostic and therapeutic target.