Orthopaedic Research Lab, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada; McGill Scoliosis and Spine Group, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada
Orthopaedic Research Lab, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada; McGill Scoliosis and Spine Group, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada
Matthew Mannarino
Orthopaedic Research Lab, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada; McGill Scoliosis and Spine Group, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada
Oded Rabau
McGill Scoliosis and Spine Group, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada; Shriner’s Hospital for Children, 1003 Decarie Blvd, Montreal, Canada
Jean A Ouellet
McGill Scoliosis and Spine Group, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada; Shriner’s Hospital for Children, 1003 Decarie Blvd, Montreal, Canada
Orthopaedic Research Lab, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada; McGill Scoliosis and Spine Group, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada; Shriner’s Hospital for Children, 1003 Decarie Blvd, Montreal, Canada
Cellular senescence is a contributor to intervertebral disc (IVD) degeneration and low back pain. Here, we found that RG-7112, a potent mouse double-minute two protein inhibitor, selectively kills senescent IVD cells through apoptosis. Gene expression pathway analysis was used to compare the functional networks of genes affected by RG-7112, a pure synthetic senolytic with o-Vanillin a natural and anti-inflammatory senolytic. Both affected a functional gene network related to cell death and survival. O-Vanillin also affected networks related to cell cycle progression as well as connective tissue development and function. Both senolytics effectively decreased the senescence-associated secretory phenotype (SASP) of IVD cells. Furthermore, bioavailability and efficacy were verified ex vivo in the physiological environment of degenerating intact human discs where a single dose improved disc matrix homeostasis. Matrix improvement correlated with a reduction in senescent cells and SASP, supporting a translational potential of targeting senescent cells as a therapeutic intervention.
