A growing body of work implicates the accumulation of senescent cells in degeneration of function and structure in the discs that separate vertebrae in the spine. This is a prevalent issue, causing pain and loss of function. The ability to restore lost function is limited at best, but clearance of senescent cells via senolytic drugs has shown promise in animal studies of degenerative disc disorders. Here, researchers employ a novel senolytic approach to produce beneficial outcomes in mice.
Low back pain (LBP) is often related to IVD degeneration and is the number one global cause of years lived with disability. The personal costs of reduced quality of life and the economic cost to healthcare systems are enormous. Senescent cells (SnCs) accumulate in degenerating intervertebral discs (IVDs) and are proposed to directly contribute to disease progression and back pain. Senescence-associated secretory phenotype (SASP) factors secreted by SnCs generate a pro-inflammatory environment that accelerates the breakdown of the extracellular matrix (ECM) and worsens IVD degeneration.
The senolytic drugs o-vanillin and RG-7112 remove human senescent IVD cells and reduce SASP factor release from cells and intact IVDs. The senolytic drug RG-7112 is a p53/MDM2 complex inhibitor. o-Vanillin is a natural senolytic and senomorphic substance that has been shown to reduce senescence burden and SASP factor release and to improve tissue homeostasis in human IVDs, indicating that they could potentially reduce pain. Here we treated sparc-/- mice, an animal model of LBP, with oral administration of o-vanillin and RG-7112 as single or combination treatments. Treatment reduced LBP and SASP factor release and removed SnCs from the IVD and spinal cord. Treatment also lowered degeneration scores in the IVDs, improved vertebral bone quality, and reduced the expression of pain markers in the spinal cord.
Together, our data suggest RG-7112 and o-vanillin as potential disease-modifying drugs for LBP and other painful disorders linked to cell senescence.
Link: https://doi.org/10.1126/sciadv.adr1719
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