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.
Arthritis Rheumatol
; 73(8): 1451-1460, 2021 08.
Article
en En
| MEDLINE
| ID: mdl-33559324
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 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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Osteoartritis
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Proteínas de Fase Aguda
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Glicoproteínas de Membrana
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Proteínas Portadoras
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Mediadores de Inflamación
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Receptores de Lipopolisacáridos
/
Receptores Toll-Like
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Arthritis Rheumatol
Año:
2021
Tipo del documento:
Article