Senolytics Improve Microvasculature and Slow Disc Degeneration in Mice

Senolytic therapies to clear lingering senescent cells in aged tissues improve a great many age-related conditions in animal models, among them intervertebral disc degeneration. Researchers here note the association of this effect with the deterioration of the microvasculature that delivers nutrients to disc tissue. As always, it is a challenge to determine whether or not the mechanism is significant in comparison to, say, the effects of inflammatory signaling generated by senescent cells on the same disc tissues. Nonetheless, the small blood vessel networks present throughout the body do deteriorate with age, their density decreasing, and thus also their ability to supply tissues with oxygen and nutrients. This is likely harmful to cell and tissue function throughout the body, and so it is interesting to see senescent cells implicated specifically in this issue.

With the increase of age, the function and interaction of three unique intervertebral disc (IVD) compartments: the central nucleus pulposus (NP), the circumferential annulus fibrosus (AF), and the cranial and caudal cartilaginous endplates (CEP) continue to deteriorate, which is difficult to avoid. Normal IVD is the largest avascular structure in human body and exchanges metabolites via diffusion from the adjacent capillary bed penetrating the subchondral bone of the endplate and the capillaries around the fibrous ring. The main nutrient supply of the IVD comes from the bony endplate vasculature, and material exchange between the vertebral body and the IVD is carried out through the diffusion of the cartilaginous endplate, which is the nutrient supply route of the disc cells.

As life span increases, so does the cartilaginous endplate osteosclerosis changes, accompany with the number of microvessels under the bony endplate gradually decreases, and the permeability disappears, resulting in the imbalance of energy metabolism of nucleus pulposus cells. Consequently, microvessels under the bony endplate and nutrient availability at the bone-disc interface decreases may be a key factor of intervertebral disc degeneration (IDD) that could not be neglected.

During IVD degenerative process, there are inevitable interactions between the human IVD cells and adjacent non-IVD cells, including endothelial cells (ECs) which play a major part in vascular structure formation. The senescent vascular endothelial cellular accumulation, which leads to the altered cellularity, vascular regression, and extracellular matrix composition, might set the IVD on a slow course toward degeneration. Additionally, there is a positive association of the vascular endothelial cellular senescence with the decrease of microvasculature in the marrow space of the bony endplate, which can hinder transport from nutrient supply to the disc or result in changes in cell phenotype, even death.

In this study, the relationships between endothelial cellular senescence in the marrow space of the bony endplate and IVD degeneration were investigated using the aged mice model. Preliminary results showed that senolytics alleviate endothelial cellular senescence in the marrow space of the bony endplate as evidenced by reduced senescence-associated secretory phenotype. In the aged mice model, we found decreased height of IVD accompanied by vertebral bone mass loss and obvious changes to the endplate subchondral vasculature, which may lead to the decrease in nutrition transport into IVD. These findings may provide evidence that senolytics can eliminate the senescent cells and facilitate microvascular formation in the marrow space of the bony endplate. Targeting senescent cellular clearance mechanism to increase nutrient supply to the avascular disc suggests a potential treatment value of senolytics for IVD degenerative diseases.


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