Abstract
Osteoarthritis (OA) is a common debilitating joint disorder, there’s still no available disease-modifying drug for OA currently. This study aims to explore the role of TAK1 in OA pathogenesis and therapeutic efficiency of TAK1 inhibition for OA. The contribution of TAK1 to OA pathogenesis was investigated by intra-articular injection of TAK1-encoding adenovirus in rats. TAK1 inhibitor 5Z-7-induced expression changes of extracellular matrix (ECM)-related genes were detected by real-time PCR. The protective effect of 5Z-7 against OA progression was evaluated in a post-traumatic OA rat model. Our results showed that intra-articular injection of Ad-Tak1 induced cartilage destruction and OA-related cytokine secretion in rat joints. TAK1 inhibition by 5Z-7 efficiently blocked NF-κB, JNK and p38 pathways activation in OA chondrocytes and synoviocytes, Meanwhile, 5Z-7 significantly decreased the expression of matrix-degrading enzymes and pro-inflammatory cytokine, while increased ECM protein expression, which are all crucial components in OA. 5Z-7 also ameliorated ECM loss in OA cartilage explants. More importantly, 5Z-7 significantly protected against cartilage destruction in a rat model of OA. In conclusion, our findings provide the first in vivo evidence that TAK1 contributes to OA by disrupting cartilage homeostasis, thus represents an ideal target for OA treatment, with 5Z-7 as a candidate therapeutic.
Highlights
Osteoarthritis (OA) is a common degenerative joint disorder, in which a variety of aetiological risk factors and pathophysiological processes contribute to its progressive nature
We report that intra-articular overexpression of Transforming growth factor β-activated kinase 1 (TAK1) leads to typical OA pathological changes in rat knees, and TAK1 inhibition by a small molecular inhibitor 5Z-7 protects against osteoarthritic cartilage degradation and synovial inflammation via regulating a series of extracellular matrix (ECM)-related genes
To evaluate sub-tissue distribution of the adenovirus, frozen sections of rat knee joints were examined by confocal microscopy 24 hours after injection of green fluorescent protein (GFP)-tagged Ad-Tak[1], as shown in Fig. 1a, GFP fluorescence was observed in cartilage, synovium, as well as meniscus, indicating that Ad-Tak[1] was able to penetrate and efficiently transduce cells in the above three tissue types
Summary
Osteoarthritis (OA) is a common degenerative joint disorder, in which a variety of aetiological risk factors and pathophysiological processes contribute to its progressive nature. OA is primarily characterized by cartilage destruction, which are mainly contributed by two pathways: upregulation of matrix degradation enzymes and downregulation of cartilage-specific extracellular matrix (ECM) proteins[1]. We report that intra-articular overexpression of TAK1 leads to typical OA pathological changes in rat knees, and TAK1 inhibition by a small molecular inhibitor 5Z-7 protects against osteoarthritic cartilage degradation and synovial inflammation via regulating a series of ECM-related genes. These results suggest that TAK1 is an attractive therapeutic target in OA and its inhibitor 5Z-7 presents a promising candidate for OA drug development
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