Inhibition of TRADD ameliorates chondrocyte necroptosis and osteoarthritis by blocking RIPK1-TAK1 pathway and restoring autophagy.

Osteoarthritis (OA) is an age-related disease characterized by cartilage degeneration. TNFR1-associated death domain protein (TRADD) is a key upstream molecule of TNF-α signals but its role in OA pathogenesis is unknown. This study aimed to verify that whether inhibition of TRADD could protect against chondrocyte necroptosis and OA, and further elucidate the underlying mechanism. We demonstrated that TNF-α-related OA-like phenotypes including inflammation response, extracellular matrix degradation, apoptosis, and necroptosis in chondrocytes were inhibited by TRADD deficiency. Furthermore, TRADD interacted with TRAF2 and knockdown of TRADD suppressed the activation of RIPK1-TAK1-NF-κB signals and restored impaired autophagy. ICCB-19, the selective inhibitor of TRADD, also attenuated necroptosis in chondrocytes. Mechanismly, ICCB-19 blocked the phosphorylation of TAK1-NF-κB signals and restored impaired autophagy, whereas inhibiting autophagic process with 3-Methyladenine compromised these effects of ICCB-19. The in vivo study showed that the intra-articular injection of ICCB-19 rescued the expression of collagen alpha-1(II) chain and LC3, and mitigated the cartilage degeneration of OA mice. This study demonstrates that TRADD mediates TNF-α-induced necroptosis and OA-like phenotypes of chondrocytes and suggests that ICCB-19 suppresses chondrocyte damage and cartilage degeneration by inhibiting TNF-α-TRADD-mediated signals and dysregulation of autophagy in chondrocytes. ICCB-19 may serve as an important option for OA therapy.