1. Inhibitory Effect of a Tankyrase Inhibitor on Mechanical Stress-Induced Protease Expression in Human Articular Chondrocytes.
- Author
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Hotta Y, Nishida K, Yoshida A, Nasu Y, Nakahara R, Naniwa S, Shimizu N, Ichikawa C, Lin D, Fujiwara T, and Ozaki T
- Subjects
- Humans, beta Catenin metabolism, Cells, Cultured, Chondrocytes drug effects, Chondrocytes metabolism, Interleukin-1beta metabolism, Matrix Metalloproteinase 13 genetics, Matrix Metalloproteinase 13 metabolism, NF-kappa B metabolism, Peptide Hydrolases drug effects, Peptide Hydrolases metabolism, Stress, Mechanical, Cartilage, Articular metabolism, Osteoarthritis metabolism, Tankyrases antagonists & inhibitors
- Abstract
We investigated the effects of a Tankyrase (TNKS-1/2) inhibitor on mechanical stress-induced gene expression in human chondrocytes and examined TNKS-1/2 expression in human osteoarthritis (OA) cartilage. Cells were seeded onto stretch chambers and incubated with or without a TNKS-1/2 inhibitor (XAV939) for 12 h. Uni-axial cyclic tensile strain (CTS) (0.5 Hz, 8% elongation, 30 min) was applied and the gene expression of type II collagen a1 chain ( COL2A1 ), aggrecan ( ACAN ), SRY-box9 ( SOX9 ), TNKS-1/2 , a disintegrin and metalloproteinase with thrombospondin motifs-5 ( ADAMTS-5 ), and matrix metalloproteinase-13 ( MMP-13 ) were examined by real-time PCR. The expression of ADAMTS-5, MMP-13, nuclear translocation of nuclear factor-κB (NF-κB), and β-catenin were examined by immunocytochemistry and Western blotting. The concentration of IL-1β in the supernatant was examined by enzyme-linked immunosorbent assay (ELISA). TNKS-1/2 expression was assessed by immunohistochemistry in human OA cartilage obtained at the total knee arthroplasty. TNKS-1/2 expression was increased after CTS. The expression of anabolic factors were decreased by CTS, however, these declines were abrogated by XAV939. XAV939 suppressed the CTS-induced expression of catabolic factors, the release of IL-1β, as well as the nuclear translocation of NF-κB and β-catenin. TNKS-1/2 expression increased in mild and moderate OA cartilage. Our results demonstrated that XAV939 suppressed mechanical stress-induced expression of catabolic proteases by the inhibition of NF-κB and activation of β-catenin, indicating that TNKS-1/2 expression might be associated with OA pathogenesis.
- Published
- 2024
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