Lipopolysaccharide Binding Protein and CD14, Cofactors of Toll‐like Receptors, Are Essential for Low‐Grade Inflammation–Induced Exacerbation of Cartilage Damage in Mouse Models of Posttraumatic Osteoarthritis

Abstract

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 inflammationassociated 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 lowgrade 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.

Integrating Network Pharmacology and Experimental Validation to Explore the Key Mechanism of Gubitong Recipe in the Treatment of Osteoarthritis

“…The top 40 pathways of KEGG results were visualized with a dot plot ( Figure 3(a) ). KEGG results indicated that the PI3K/AKT pathway [ 35 ], Toll-like receptor pathway [ 36 ], NOD-like receptor pathway [ 37 ], TNF pathway [ 38 ], and HIF-1 pathway [ 39 ] were closely related to OA. A network of 6 OA-related pathways and their corresponding targets is shown in Figure 3(b) .…”

Association of low-grade inflammation caused by gut microbiota disturbances with osteoarthritis: A systematic review

“…The final analysis included 12 studies, 6 of which were animal studies ( 24 – 29 ) and 6 were clinical studies ( 5 , 30 – 34 ). Regarding clinical trials, 4 were non-randomized observational studies ( 5 , 30 , 33 , 34 ) and 2 were randomized clinical trials ( 31 , 32 ).…”

The Role of Rumen Microbiota and Its Metabolites in Subacute Ruminal Acidosis (SARA)-Induced Inflammatory Diseases of Ruminants

“…A large body of studies has demonstrated a significant link between a mild proinflammatory state and many diseases. IGL contributes to the development of many diseases, such as metabolic syndrome (MetS), nonalcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (T2DM) and osteoarthritis [ 55 , 56 , 57 , 58 ]. Meanwhile, studies have shown that these diseases are accompanied by gut microbiota disorder [ 59 , 60 , 61 , 62 ].…”