objective: Osteoarthritis (OA) is initiated by pathogenic factors produced by multiple stimuli, including mechanical stress, metabolic stress, and/or inflammaging. This study was undertaken to identify novel low-grade inflammation-associated pathogenic mediators of OA.
methods: Candidate pathogenic molecules were screened using microarray data obtained from chondrocytes exposed to OA-associated catabolic factors. In mice with OA generated by destabilization of the medial meniscus (DMM), low-grade inflammation was induced by a high-fat diet or endotoxemia. Functions of candidate molecules in OA pathogenesis were examined using primary-culture chondrocytes from mice with DMM-induced OA, following intraarticular i... More
objective: Osteoarthritis (OA) is initiated by pathogenic factors produced by multiple stimuli, including mechanical stress, metabolic stress, and/or inflammaging. This study was undertaken to identify novel low-grade inflammation-associated pathogenic mediators of OA.
methods: Candidate pathogenic molecules were screened using microarray data obtained from chondrocytes exposed to OA-associated catabolic factors. In mice with OA generated by destabilization of the medial meniscus (DMM), low-grade inflammation was induced by a high-fat diet or endotoxemia. Functions of candidate molecules in OA pathogenesis were examined using primary-culture chondrocytes from mice with DMM-induced OA, following intraarticular injection of adenovirus expressing the candidate gene. Specific functions of candidate genes were evaluated using whole-body gene-knockout mice.
results: Bioinformatics analysis identified multiple candidate pathogenic factors that were associated with low-grade inflammation, including components of the Toll-like receptor (TLR) signaling pathways (e.g., TLR-2, TLR-4, lipopolysaccharide binding protein [LBP], and CD14). Overexpression of the individual TLR signaling components in mouse joint tissue did not alter cartilage homeostasis. However, the low-grade inflammation induced by a high-fat diet or endotoxemia markedly enhanced posttraumatic OA cartilage destruction in mice, and this exacerbation of cartilage destruction was significantly abrogated in LBP and CD14 mice. Additionally, LBP and CD14 were found to be necessary for the expression of matrix-degrading enzymes in mouse chondrocytes treated with proinflammatory cytokines.
conclusion: LBP and CD14, which are accessory molecules of TLRs, are necessary for the exacerbation of posttraumatic OA cartilage destruction resulting from low-grade inflammation, such as that triggered by a high-fat diet or endotoxemia.
