Abstract
Anterior cruciate ligament (ACL) transection surgery in the minipig induces post-traumatic osteoarthritis (PTOA) in a pattern similar to that seen in human patients after ACL injury. Prior studies have reported the presence of cartilage matrix-degrading proteases, such as Matrix metalloproteinase-1 (MMP-1) and A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4), in the synovial fluid of injured or arthritic joints; however, the tissue origin of these proteases is unknown. The objective of this study was to identify transcriptional processes activated in the synovium after surgical induction of PTOA with ACL transection, and to determine if processes associated with proteolysis were enriched in the synovium after ACL transection. Unilateral ACL transection was performed in adolescent Yucatan minipigs and synovium samples were collected at 1, 5, 9, and 14 days post-injury. Transcriptome-wide gene expression levels were determined using bulk RNA-Sequencing in the surgical animals and control animals with healthy knees. The greatest number of transcripts with significant changes was observed 1 day after injury. These changes were primarily associated with cellular proliferation, consistent with measurements of increased cellularity of the synovium at the two-week time point. At five to 14 days, the expression of transcripts relating to proteolysis and cartilage development was significantly enriched. While protease inhibitor-encoding transcripts (TIMP2, TIMP3) represented the largest fraction of protease-associated transcripts in the uninjured synovium, protease-encoding transcripts (including MMP1, MMP2, ADAMTS4) predominated after surgery. Cartilage development-associated transcripts that are typically not expressed by synovial cells, such as ACAN and COMP, were enriched in the synovium following ACL-transection. The upregulation in both catabolic processes (proteolysis) and anabolic processes (cartilage development) suggests that the synovium plays a complex, balancing role in the early response to PTOA induction.
Highlights
Knee injuries, disruption of the anterior cruciate ligament (ACL), drastically increase the risk for post-traumatic osteoarthritis (PTOA) in human patients [1,2,3] and animal models [4, 5]
Clinical studies have supported catabolic changes in the articular cartilage occurring within the first few weeks of injury by identifying the breakdown products of articular cartilage in the synovial fluid, such as C-terminus of 3⁄4 fragment short of type II collagen (C1, C2) after ACL injury or C-terminus of 3⁄4 fragment long of type II collagen (C2C) after ACL reconstruction surgery[6, 7], as well as high levels of pro-inflammatory cytokines and extracellular matrix fragments in the synovial fluid of injured human knee joints[7,8,9,10,11,12]
The synovium is commonly regarded as a source of pro-inflammatory cytokines [19,20,21], which could affect articular cartilage health through the synovial fluid, facilitating the proteolysis of the articular cartilage extracellular matrix (ECM)
Summary
Disruption of the anterior cruciate ligament (ACL), drastically increase the risk for post-traumatic osteoarthritis (PTOA) in human patients [1,2,3] and animal models [4, 5]. Clinical studies have supported catabolic changes in the articular cartilage occurring within the first few weeks of injury by identifying the breakdown products of articular cartilage in the synovial fluid, such as C-terminus of 3⁄4 fragment short of type II collagen (C1, C2) after ACL injury or C-terminus of 3⁄4 fragment long of type II collagen (C2C) after ACL reconstruction surgery[6, 7], as well as high levels of pro-inflammatory cytokines and extracellular matrix fragments in the synovial fluid of injured human knee joints[7,8,9,10,11,12]. Early anti-inflammatory treatment with intraarticular triamcinolone acetonide injections prevented the increase in collagen fragments (C-telopeptide of type II collagen (CTX-II)) in the synovial fluid of human patients with acute ACL injury[24], and C1 and 2C fragments in minipigs following ACL transection surgery[25], further supporting the link between synovial inflammation and cartilage ECM proteolysis. The early timing of synovial changes, and the optimum timing for possible interventions, remains unknown
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