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Posttraumatic activation of the catabolic cascade plays a major role in degradation of cartilage. Interleukin-1 β  (IL-1 β ), a primary instigator in the catabolic axis, is upregulated in chondrocytes following injury. IL-1 β  activates key degradative enzymes, including MMPs and aggrecanases, and other proinflammatory mediators such as PGE 2  which contribute to ECM breakdown. Posttranscriptional silencing of IL-1 β  by RNA interference (RNAi) may drive a reduction in IL-1 β . We hypothesized that transduction of chondrocytes using rAAV2 expressing a short hairpin RNAi motif targeting IL-1 β  (shIL-1 β ) would significantly decrease IL-1 β  expression and, in turn, decrease expression of other catabolic enzymes. Chondrocyte cultures were transduced with rAAV2-tdT-shIL-1 β  in serum-free media. The fluorescent protein, tdTomato, was used to determine transduction efficiency via flow cytometry and fluorescent microscopy. Cells were stimulated with lipopolysaccharide (LPS) 48 hours following transduction. After 24-hour stimulation, supernatants were collected for cytokine analysis, and cells lysed for gene expression analysis. IL-1 β  knockdown led to significantly decreased expression of  IL-1β ,  TNF-α , and  ADAMTS5 . PGE 2  synthesis was also significantly downregulated. Overall, effective silencing of IL-1 β  using rAAV2 vector expressing a short hairpin IL-1 β  knockdown sequence was shown. Additionally, significant downstream effects were evident, including decreased expression of  TNF-α  and  ADAMTS5 . Targeted silencing of catabolic cytokines may provide a promising treatment avenue for osteoarthritic (OA) joints.

RNA Interference Mediated Interleukin-1β Silencing in Inflamed Chondrocytes Decreases Target and Downstream Catabolic Responses