![]() As there were no differences in gene expression or histology among the surgical groups, and no macroscopic cartilage damage in any group at the 1- or 4-week time point, the data from the three surgical groups and two time points were pooled to improve our ability to detect significant correlations between the inflammatory cytokines or MMPs and the tissue RNA expression of the genes for those proteins. We elected to begin to explore this question by looking for correlations between the gene expression of these mediators, as previously determined using RNA-Seq, with newly acquired synovial fluid protein level data to determine if either the articular cartilage or synovium were reasonable candidates as the contributors. Possibilities include secretion by the articular cartilage, synovium, another intra-articular tissue, or a transudate of serum. However, the primary tissue sources for these inflammatory mediators are unknown. Prior studies have reported an increase in the concentrations of inflammatory cytokines and MMPs in the synovial fluid following joint injury, particularly for IL-1Ra, IL-4, IL-6, IL-12, and IL-18. Within the first four weeks after transection of the anterior cruciate ligament (ACL) in the porcine model, a post-surgical inflammatory response has been noted, consisting of changes in the histology of the synovium and cartilage, as well as in the gene expression of the two tissues, regardless of whether a concomitant ACL restoration or reconstruction procedure was performed. While inflammation has long been thought to play an essential role in the post-operative course, the primary tissue sources for the different inflammatory cytokines and matrix metalloproteinases (MMPs) remain to be elucidated. Post-surgical or post-injury joint inflammation has been implicated in the development of prolonged post-operative pain, arthrofibrosis, and osteoarthritis, with the interleukins and matrix metalloproteinases found in the synovial fluid of inflamed joints thought to play key roles in these manifestations. In developing treatments for post-surgical inflammation, the synovium may therefore be a promising target for modulating inflammatory mediators such as MMP-13 and IL-6 in the synovial fluid. The synovium may be an important source of MMP-13 and IL-6, and the articular cartilage may be an important source of IL-1α in post-surgical inflammation. Synovial fluid levels of MMP-13 and IL-6 were significantly correlated with synovial gene expression (P=.003 and P<.001 respectively), while IL-1α levels were significantly correlated with articular cartilage gene expression (P=.037). Linear regressions were used to evaluate the relationships between synovial fluid protein levels and the previously reported gene expression levels in the articular cartilage and synovium from the same animal cohort. In this study, 36 Yucatan minipigs underwent ACL surgery, and a custom multiplex assay was used to measure synovial fluid protein levels of MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-12, MMP-13, IL-1α, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-18, GM-CSF, and TNFα in 18 animals at 1 and 4 weeks after surgery. Prior work in a porcine model has demonstrated that anterior cruciate ligament (ACL) surgery leads to significant changes in early gene expression in the synovium and articular cartilage, which are the same whether concomitant ligament restoration is performed or not. The primary source of synovial fluid inflammatory mediators is currently unknown and may include different tissues comprising the joint, including the synovium and articular cartilage.
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