The potential role of synovial T-cell infiltration following knee joint injury in symptoms and progression to osteoarthritis.

Abstract

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. We undertook detailed temporal flow-cytometric and mRNA expression analysis in mice after sham or medial-meniscal-destiblization (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. OA-inducing/DMM and non-OA-inducing/Sham surgery had identical synovial monocyte/macrophage number, activation and polarization. The number and activation of synovial (not splenic or peripheral-blood) CD4⁺ and CD8⁺ lymphocytes was increased from 1-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 post-injury and late-OA CD3/CD8 T-cell responses in synovial tissues from patients, identified an association between CD8 and early post-injury 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 post-injury T-cell responses may be associated with long-term OA pathology. We identify a hitherto unappreciated pathophysiological role of acute T-cell activation after joint injury in long-term post-traumatic OA risk, providing a novel diagnostic and therapeutic target.