AZ-628 delays osteoarthritis progression via inhibiting the TNF-α-induced chondrocyte necroptosis and regulating osteoclast formation

As a degenerative disease, the pathogenesis and treatment of osteoarthritis (OA) are still being studied. The prevailing view is that articular cartilage dysfunction plays an essential role in the development of osteoarthritis. Similarly, dynamic bone remodeling dramatically influences the development of osteoarthritis. The inflamma-tory response is caused by the overexpression of inflammatory factors, among which tumor necrosis factor-alpha is one of the main causes of OA, and its sources include the secretion of chondrocytes themselves and osteoclast secretion of subchondral bone. Moreover, TNF-alpha-induced activation of RIP1, RIP3, and MLKL has been shown to play an important role in cell necroptosis and inflammatory responses. In vitro, AZ-628 alleviates chondrocyte inflammation and necroptosis by inhibiting the NF-kappa B signaling pathway and RIP3 activation instead of RIP1 activation. AZ-628 also reduces osteoclast activity, proliferation and differentiation, and release of inflammatory substances by inhibiting autophagy, MAPK, and NF-kappa B pathways. Similarly, the in vivo study demonstrated that AZ-628 could inhibit chondrocyte breakdown and lower osteoclast formation and bone resorption, thereby slowing down subchondral bone changes induced by dynamic bone remodeling and reversing the progression of osteoarthritis in mice. The results of this study indicate that AZ-628 could be used to treat OA by inhibiting chondrocyte necroptosis and regulating osteoclast formation.