Directed elimination of senescent cells attenuates development of osteoarthritis by inhibition of c-IAP and XIAP

Aging drives the accumulation of senescent cells (SnCs) by secreting factors that cause the senescence-associated secretory phenotype (SASP), including stem cells in the bone marrow, which contribute to aging-related bone degradation. Osteoarthritis (OA) is a serious chronic injury disease, and increasing age is a major risk factor. The accumulation of SnCs may accelerate the development of OA, and the accumulation of SnCs may benefit from its resistance to apoptotic stimuli. Therefore, local elimination of SnCs could be a promising treatment for OA. Apoptosis inhibitor protein (IAP) is an important antiapoptotic protein in vivo. AT-406 is a small molecule inhibitor of the IAP genes and also regulates the transcription of several genes. Here, we show that SnCs upregulate the antiapoptotic proteins c-IAP1, c-IAP2 and XIAP.The combined inhibition of c-IAP1, c-IAP2 and XIAP using siRNA or AT-406 specifically induce the apoptosis of SnCs.In addition, XIAP and STX17 bind to each other to regulate the fusion of autophagosomes and lysosomes in SnCs, which in turn, affects the fate of SnCs. It is worth noting that the clearance of SnCs attenuated the secretion of SASP and created a proregenerative environment. Most importantly, local clearance of SnCs significantly attenuated the progression of osteoarthritis in rats without significant toxic effects. Thus, local elimination of SnCs may be a potential treatment for OA. This is the first report of inhibition of IAPs for clearing SnCs and suggests that eradication of SnCs may be a new strategy for the treatment of age-related diseases.