Research Paper Volume 12, Issue 13 pp 12750—12770
Navitoclax (ABT263) reduces inflammation and promotes chondrogenic phenotype by clearing senescent osteoarthritic chondrocytes in osteoarthritis
- 1 Center for Joint Surgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing 400038, People’s Republic of China
- 2 Department of Orthopedics, West China Hospital, West China School of Medicine, Sichuan University, Chengdu 610041, People’s Republic of China
Received: September 27, 2019 Accepted: March 24, 2020 Published: July 1, 2020https://doi.org/10.18632/aging.103177
How to Cite
Copyright © 2020 Yang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Cell senescence is a chronic process associated with age-related degenerative diseases such as osteoarthritis (OA). Senescent cells (SnCs) accumulate in the articular cartilage and synovium, leading to OA pathologies. The accumulation of SnCs in the cartilage results in a senescence-associated secretory phenotype (SASP) and age-related inflammation and dysfunction. Selective removal of SnCs by senolytic agent as a therapeutic strategy has been developed recently. In this study, we examined the ability of the senolytic drug ABT263 (navitoclax) to clear SnCs and further evaluated the therapeutic effect of ABT263 on post-traumatic OA. Monolayer and 3D pellet cultured osteoarthritic chondrocytes were used to evaluate the effect of ABT263 in vitro and a DMM rat model was established for in vivo experiments. We found that ABT263 reduced the expression of inflammatory cytokines and promoted cartilage matrix aggregation in OA chondrocyte pellet culture by inducing SnC apoptosis. Moreover, OA pathological changes in the cartilage and subchondral bone in post-traumatic OA rat were alleviated by ABT263 intra-articular injection. These results demonstrated that ABT263 not only improves inflammatory microenvironment but also promotes cartilage phenotype maintenance in vitro. Furthermore, ABT263 might play a protective role against post-traumatic OA development. Therefore, strategies targeting SnC elimination might be promising for the clinical therapy of OA.
OA: osteoarthritis; SnCs: senescent cells; ROS: reactive oxygen species; SA-β-Gal: senescence-associated β-galactosidase; Cdkn2a: cyclin-dependent kinase inhibitor 2a; SASP: senescence-associated secretory phenotype; IR: ionizing radiation; cDNA: complementary DNA; DMM: destabilization of the medial meniscus; OARSI: Osteoarthritis Research Society International; HMGB1: high-mobility-group box 1; GAGs: glycosaminoglycan; HUVECs: human umbilical vein epithelial cells; MEFs: murine embryonic fibroblasts; MSCs: mesenchymal stem cells.