Stone, L. S. | Search bioRxiv

bioRxiv2024

Senolytic Treatment for Low Back Pain.

Senescent cells (SnCs) accumulate due to aging and external cellular stress throughout the body. They adopt a senescence-associated secretory phenotype (SASP) and release inflammatory, and degenerative factors that actively contribute to age-related diseases such as low back pain (LBP). The senolytics, o-Vanillin and RG-7112, remove senescent human intervertebral (IVD) cells and reduce SASP release, but it is not known if they can treat LBP. sparc-/- mice, with LBP, were treated orally with 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 score in the IVDs, improved vertebral bone quality, and reduced the expression of pain markers in the spinal cord. The result indicates that RG-7112 and o-Vanillin with the combination treatment providing the strongest effect are potential disease-modifying drugs for LBP and other painful disorders where cell senescence is implicated. One Sentence Summary: Senolytics drugs can reduce back pain

cell biology↗

bioRxiv2023

Environmentally stressed human nucleus pulposus cells trigger the onset of discogenic low back pain

Low back pain (LBP) is often associated with the degeneration of human intervertebral discs (IVDs). However, the pain-inducing mechanism in degenerating discs remains to be elucidated. Here, we identified a subtype of locally residing nucleus pulposus cells (NPCs), generated by the environmental stress in degenerating discs, that triggered the onset of discogenic LBP. Single-cell transcriptomic analysis of human tissues showed a strong correlation between this specific pain-triggering subtype and the pain conditions in human degenerated discs. Next, we recreated this pain-triggering subtype by applying known exogenous stressors to healthy NPCs in vitro. The recreated pain phenotype activated functional sensory neurons response in vitro and induced local inflammatory responses, hyperalgesia, and mechanical sensitivity in a healthy rat IVD in vivo. Our findings provide strong evidence of a previously unknown pain-inducing mechanism mediated by NPCs in degenerating IVDs. This newly defined pathway will aid in the development of NPC-targeted therapeutic strategies for clinically unmet need to attenuate discogenic LBP. One Sentence SummaryDiscogenic low back pain can be initiated by a stress-induced subtype of nucleus pulposus cells present in human degenerating intervertebral discs

molecular biology↗