J. Cheng (Beijing, CN)
Institute of Sports Medicine Peking University Third HospitalPresenter Of 1 Presentation
12.2.10 - Targeted Inhibition of TAK1 Prevents Inflammation-Related Cartilage Degradation in Osteoarthritis
Abstract
Purpose
Osteoarthritis (OA) is a common debilitating joint disorder, there’s still no available disease-modifying drug for OA currently. TGF-β-activated kinase 1 (TAK1) is a key intermediate in immune-related signal transduction induced by TGF-β and proinflammatory stimuli such as IL-1β and TNF-α. However, the role of TAK1 in OA pathogenesis and the therapeutic efficiency of TAK1 inhibition for OA remains to be elucidated. This study aims to clarify the function of TAK1 in OA process and its mechanism, and systematically elucidate the delaying effect of targeted TAK1 inhibition towards OA.
Methods and Materials
The contribution of TAK1 to OA pathogenesis was investigated by intra-articular injection of TAK1-encoding adenovirus in rats. The suppressive function of TAK1 inhibitor 5Z-7 on NF-κB, JNK and p38 MAPK pathway activation in both chondrocytes and synoviocytes was determined by western blot and luciferase reporter assay. 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.
Results
Intra-articular injection of Ad-Tak1 significantly induced inflammation-related cartilage destruction in rat joints. TAK1 inhibition by 5Z-7 significantly blocked NF-κB, JNK and p38 pathway activation induced by IL-1β in normal chondrocytes and synoviocytes, and effectively reduced basal activation level of the above pathways in OA chondrocytes and synoviocytes. 5Z-7 also significantly downregulated the expression of a series of matrix-degrading enzymes and inflammatory cytokines, while upregulated the expression of ECM proteins, which are all crucial components in OA. Furthermore, 5Z-7 also ameliorated ECM loss in OA cartilage explants. More importantly, the application of 5Z-7 significantly protected against OA-related pathological changes in a rat model of OA.
Conclusion
Our findings have provided 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.