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Senotherapeutic drugs for human intervertebral disc degeneration and low back pain
Hosni Cherif1,2, Daniel G Bisson1,2, Matthew Mannarino1,2
1Orthopaedic Research Lab, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada.
Abstract:
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.
Insights
Cellular senescence drives intervertebral disc degeneration and low back pain. New senolytic drugs RG-7112 and o-Vanillin selectively eliminate senescent cells, reduce inflammation, and improve disc health.
Area of Science:
- Biomedical Sciences
- Regenerative Medicine
- Cell Biology
Background:
- Cellular senescence contributes to intervertebral disc (IVD) degeneration and low back pain.
- Senescent cells accumulate in degenerating IVDs and promote inflammation via the senescence-associated secretory phenotype (SASP).
Purpose of the Study:
- To investigate the senolytic potential of RG-7112 and o-Vanillin in IVD cells.
- To evaluate the impact of these senolytics on SASP and matrix homeostasis in degenerating human IVDs.
Main Methods:
- Cellular senescence induction and treatment with RG-7112 and o-Vanillin.
- Gene expression pathway analysis to identify affected functional networks.
- Ex vivo assessment of senolytic efficacy in human IVD organ cultures.
Main Results:
- RG-7112 and o-Vanillin selectively induced apoptosis in senescent IVD cells.
- Both senolytics reduced SASP and affected cell death/survival gene networks.
- O-Vanillin also impacted cell cycle and connective tissue networks.
- Ex vivo treatment improved disc matrix homeostasis and reduced senescent cell burden and SASP.
Conclusions:
- Targeting senescent cells with senolytics like RG-7112 and o-Vanillin shows therapeutic potential for IVD degeneration and low back pain.
- Senolytic treatment can restore matrix homeostasis and reduce SASP in degenerating IVDs.
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