Title |
Fibronectin fragment-induced expression of matrix metalloproteinases is mediated by MyD88-dependent TLR-2 signaling pathway in human chondrocytes
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Published in |
Arthritis Research & Therapy, November 2015
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DOI | 10.1186/s13075-015-0833-9 |
Pubmed ID | |
Authors |
Hyun Sook Hwang, Su Jin Park, Eun Jeong Cheon, Mi Hyun Lee, Hyun Ah Kim |
Abstract |
Fibronectin fragments (FN-fs) are increased in the cartilage of patients with osteoarthritis (OA) and have a potent chondrolytic effect. However, little is known about the cellular receptors and signaling mechanisms that are mediated by FN-fs. We investigated whether the 29-kDa amino-terminal fibronectin fragment (29-kDa FN-f) regulates cartilage catabolism via the Toll-like receptor (TLR)-2 signaling pathway in human chondrocytes. Small interfering RNA was used to knock down TLR-2 and myeloid differentiation factor 88 (MyD88). TLR-2 was overexpressed in chondrocytes transfected with a TLR-2 expression plasmid. The expression levels of matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13 were analyzed using quantitative real-time reverse transcription polymerase chain reactions, immunoblotting, or enzyme-linked immunosorbent assay. The effect of TLR-2 on 29-kDa FN-f-mediated signaling pathways was investigated by immunoblotting. TLR-2, TLR-3, TLR-4, and TLR-5 mRNA were significantly overexpressed in OA cartilage compared with normal cartilage, whereas no significant difference of TLR-1 mRNA expression was found. 29-kDa FN-f significantly increased TLR-2 expression in human chondrocytes in a dose- and time-dependent manner. Knockdown of TLR-2 or MyD88, the latter a downstream adaptor of TLR-2, significantly inhibited 29-kDa FN-f-induced MMP production at the mRNA and protein levels. Conversely, TLR-2 overexpression led to enhanced MMP production by 29-kDa FN-f. In addition, TLR-2 knockdown apparently inhibited 29-kDa FN-f-mediated activation of phosphorylated nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha, and p38, but not of c-Jun N-terminal kinase or extracellular signal-regulated kinase. Exposure to synovial fluid (SF) from affected joints of patients with OA elevated MMP-1, MMP-3, and MMP-13 expression markedly in primary chondrocytes without reducing cell viability. However, TLR-2 knockdown in chondrocytes significantly suppressed SF-induced MMP induction. Our data demonstrate that the MyD88-dependent TLR-2 signaling pathway may be responsible for 29-kDa FN-f-mediated cartilage catabolic responses. Our results will enhance understanding of cartilage catabolic mechanisms driven by cartilage degradation products, including FN-f. The modulation of TLR-2 signaling activated by damage-associated molecular patterns, including 29-kDa FN-f, is a potential therapeutic strategy for the prevention of cartilage degradation in OA. |
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Geographical breakdown
Country | Count | As % |
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Denmark | 2 | 3% |
United Kingdom | 1 | 2% |
Unknown | 56 | 95% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Ph. D. Student | 16 | 27% |
Researcher | 9 | 15% |
Student > Master | 7 | 12% |
Student > Bachelor | 6 | 10% |
Student > Postgraduate | 4 | 7% |
Other | 6 | 10% |
Unknown | 11 | 19% |
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Biochemistry, Genetics and Molecular Biology | 11 | 19% |
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Medicine and Dentistry | 7 | 12% |
Engineering | 6 | 10% |
Pharmacology, Toxicology and Pharmaceutical Science | 2 | 3% |
Other | 6 | 10% |
Unknown | 17 | 29% |