Expanding the Therapeutic Window for Degenerative Disc Disease

A team led by University of Pennsylvania researchers is shining light on the often-ignored outer region of spinal discs and, in the process, may well have expanded the therapeutic window for degenerative disc disease.

Their study, “Aberrant mechanosensing in injured intervertebral discs as a result of boundary-constraint disruption and residual-strain loss,” appears in the October 14, 2019 edition of Nature Biomedical Engineering. 

After finding that these cells can get “stressed out” and therefore exhibit a “subpar” healing process after injuries, the research team tested a way to temporarily interrupt this process.

Edward Bonnevie, Ph.D., a post-doctoral fellow in Penn Medicine’s McKay Orthopaedic Research Laboratory, explained the genesis of this study to OTW: “Most spine research focuses on the inner part of the disc, but our work highlights the fact that we need to treat the whole disc, and we believe doing so may lead to the identification of new targets for therapy.”

“We know that cells in the inner region undergo changes as a result of disc injury and degeneration, and researchers have tried to restore function to those cells,” Bonnevie said. “But you can think of that like trying to fill up a water balloon that already has holes—it isn’t a viable treatment option by itself.”

When the research team mimicked tissue of the outer region of discs, they saw that when an injury (slipped disc, for example) occurs and pressure is lost, the suddenly released tissue becomes disorganized. When this happens, they found (by using a small animal model) that it can stimulate generation of repair tissue that had the characteristics of scar tissue, not normal disc tissue.

Additionally, the team found that programmed cell death—known as apoptosis—occurs quickly, usually within 24 hours of the injury. This poses a challenge because, unlike other areas in the body, cells in the discs lack a blood supply and cannot easily repopulate and regenerate.

To counteract the way that disc cells respond upon pressure loss, the team tested a biological inhibitor of cell contraction, such as fasudil, which, it was hypothesized, could effectively “relax” the cells from the shock of suddenly losing their typical stretched state. Once relaxed, the cells would delay their default healing response, which has the potential to buy doctors what is called a “therapeutic window” to intervene.

Dr. Bonnevie provided additional details to OTW, “Fasudil is a ROCK [rho-associated protein kinase] inhibitor, and it works to reduce cellular contractility. It effectively reduces how much a cell tugs and pulls on its surroundings. Using a technique called traction force microscopy, we were able to show in this study that fasudil reduces how much force a cell exerts by as much as 60%.”

“By using our biomaterial-based model, we were able to observe how cells respond to an injury in the ensuing minutes to hours. Our findings suggest that although disc remodeling occurs over weeks and longer times, cells start to respond to the injury on very short time scales. Consequently, we have a better understanding on the ‘therapeutic window,’ where intervention may be needed sooner rather than later.”