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. 2019 Nov 1;9:15846. doi: 10.1038/s41598-019-52358-4

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© The Author(s) 2019

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Inhibition of NO attenuates the phosphorylation of MAP kinases and NFkB signaling, but not STAT3 signaling. (A) Time-course phosphorylation of MAP kinases, IkBa and STAT3 by LPS in the presence or absence of 1400 w, an iNOS inhibitor. Primary chondrocytes were starved overnight and pretreated with 1400 w for 15 min followed by stimulation with 1 μg/ml of LPS for indicated time. (B) Schematic diagram depicting the catabolic mechanism of chondrocytes by the breakdown of chondroitin-sulfate-based ECM. The degradation of chondroitin-sulfate can produce a new ligand for TLR2 and TLR4 such as C6S and C4S which can function as DAMPs. The activated TLRs can induce the expression of MMP-13 and ADAMTS5 through MAP kinases, NFkB and STAT3 signaling forming a positive feedback loop with iNOS-NO system. This increased MMP-13 and ADAMTS5 can amplify the degradation of ECM causing a vicious cycle of cartilage destruction. In addition, the exposure of sulfate residue in CS with negative charge can induce an increase of water content resulting in a hypertrophy-like swelling of chondrocytes.