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29-kDa FN-f inhibited autophagy through modulating localization of HMGB1 in human articular chondrocytes
Hyun Sook Hwang1,2, Min Ha Choi1,2, Hyun Ah Kim1,2,*
1Department of Internal Medicine, Hallym University Sacred Heart Hospital,
2Institute for Skeletal Aging, Hallym University
Fibronectin fragments found in synovial fluid of patients with osteoarthritis (OA) induce the catabolic responses in cartilage. Nuclear high mobility group protein Box 1 (HMGB1), a damage-associated molecular pattern, is responsible for the regulation of signaling pathways related with cell death and survival in response to various stimuli. In this study, we investigated whether 29-kDa amino-terminal fibronectin fragment (29-kDa FN-f)-induced change in HMGB1 expression influences the pathogenesis of OA through HMGB1-modulated autophagy signaling pathway. Human articular chondrocytes were enzymatically isolated from articular cartilage. The level of mRNA was measured by quantitative real-time PCR. The expression of proteins was examined by western blot analysis, immnunofluorescence assay, and enzyme-linked immunosorbent assay. Interaction of proteins was evaluated by immunoprecipitation. The HMGB1 level was significantly reduced in human OA cartilage compared to normal cartilage. Although 29-kDa FN-f significantly reduced the HMGB1 expression at the mRNA and protein levels 6 h after treatment, the cytoplasmic level of HMGB1 was increased in 29-kDa FN-f-treated chondrocytes. 29-kDa FN-f significantly inhibited the interaction of HMGB1 with Beclin-1 but increased the interaction of Bcl-2 with Beclin-1, together with decreased levels of Beclin-1 and phosphorylated Bcl-2. In addition, the level of microtubule associated protein 1 light chain 3-II, an autophagy marker, was down-regulated in 29-kDa FN-f-treated chondrocytes, whereas the effect was antagonized by mTOR knockdown. Furthermore, prolonged treatment with 29-kDa FN-f significantly increased the release of HMGB1 into the culture medium. These results demonstrated that 29-kDa FN-f inhibits chondrocyte autophagy through modulation of HMGB1 signaling pathway.
Abstract, Accepted Manuscript(in press) [Submitted on March 19, 2018, Accepted on May 4, 2018]
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