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

Abstract

Aging leads to an increase in senescent cells (SnCs), which secrete factors that contribute to the senescence-associated secretory phenotype (SASP). This phenomenon includes stem cells in the bone marrow that play a role in age-related bone deterioration. Osteoarthritis (OA) is a significant chronic condition, with advancing age as a major risk factor. The buildup of SnCs may hasten the onset of OA, benefiting from their resistance to apoptosis. Consequently, targeted removal of SnCs could represent a promising approach for OA treatment.

Apoptosis inhibitor proteins (IAPs) are critical antiapoptotic proteins in living organisms. AT-406 is a small molecule that inhibits IAP genes and influences the transcription of several others. Our research indicates that SnCs increase the expression of antiapoptotic proteins c-IAP1, c-IAP2, and XIAP. Inhibiting c-IAP1, c-IAP2, and XIAP through siRNA or AT-406 specifically induces apoptosis in SnCs. Furthermore, XIAP interacts with STX17 to regulate the fusion of autophagosomes and lysosomes in SnCs, affecting their survival.

Notably, eliminating SnCs reduces SASP secretion and fosters a pro-regenerative environment. Importantly, local clearance of SnCs significantly slowed OA progression in rats without causing major toxic effects. This study is the first to report the inhibition of IAPs for the clearance of SnCs, suggesting that targeting SnCs may be a novel strategy for treating age-related AT406 diseases.