Research topic: Identification of the molecular mechanisms associated with intervertebral disk degeneration and diskogenic pain
Research results: Identification of specific proteins and inflammatory pathways associated with symptomatic intervertebral disk degeneration
Patient care application of results: Molecular-level therapies to slow or stop low back pain related to disk degeneration
Simplified patient care application: Noninvasive treatments that can be targeted to individual disks to relieve low back pain related to symptomatic disk degeneration
Oh, my aging back
OREF grant recipient aims to take the pain out of disk degeneration
Why do some people with disk degeneration experience pain, while others with comparable deterioration suffer little or no pain? That is a question clinicians, patients and employers would like answered. In 2008, a national study found persons in the United States spent a total of 671.1 million days in bed due to back pain—much of it probably related to gradual changes in biomechanics and functionality that occur as the spine, including intervertebral disks, degenerates.1
Christopher K. Kepler, MD, MBA, assistant professor of spinal surgery in the Department of Orthopaedic Surgery at Thomas Jefferson Hospital in Philadelphia, received a 2011 Orthopaedic Research and Education Foundation (OREF) Clinician Scientist Training Grant, made possible by the Ira A. Roschelle Family Foundation. During his research fellowship, Dr. Kepler applied the funding to probe the cascade that leads to disk degeneration and sometimes results in low back pain. His ultimate goal is to design nonsurgical therapies that could either slow or stop the pain.
Why are some patients symptom-free?
“Studies show that in the United States many people with disk degeneration have no symptoms,” said Dr. Kepler. “In fact, there are more people who are free of symptoms than people who experience symptoms. We need to understand when disk degeneration becomes symptomatic, why this occurs, and, most importantly, what the specific intermediaries that link disk degeneration and pain are.”
Dr. Kepler maintains that spine surgery offers fewer successful answers for disk-related low back pain when compared to other maladies that might be treated with lumbar fusion, such as degenerative spondylolisthesis or scoliosis.
“Patients with axial back pain from disk degeneration do relatively poorly after lumbar fusion,” Dr. Kepler explained. “The line of research our laboratory is pursuing offers a great opportunity to develop alternate treatment strategies.”
To find out why symptoms occur, Dr. Kepler is first working to understand the molecular mechanisms underlying inflammatory pathways that lead to symptomatic and non-symptomatic disk degeneration. “Once we’ve identified the major players in the degenerative process,” he said, “the next step is to identify which molecular pathways seem to be differentially activated in people with symptomatic disk degeneration.”
He starts by tracking patients who are undergoing spinal fusion surgery during which a disk is removed and discarded. Working closely with fellow spine surgeon Greg Anderson, MD and Dessislava Markova, PhD, Dr. Kepler takes the discarded tissue to the lab for analysis to determine patterns between patients with and without diskogenic pain in the expression of different inflammatory cytokines and other markers of degenerative and inflammatory cascades. Then, he will extract disk cells from the tissue and create a cell culture to study how the cells respond in different environments.
“We want to learn not just how the disk cells are functioning, but also how environmental changes impact their functionality, and alter the production of inflammatory markers,” he said.
Dr. Kepler pointed out that, while the disk is exposed on 360 degrees, symptomatic herniations occur posterior to the disk. “It could be that we only notice posterior disk herniations because that’s where the spinal canal is so that’s where nerve compression occurs,” he said. “But the posterior aspect of the disk also seems to have the most abundant nerve supply, which we think is responsible for most diskogenic pain.” By looking at samples from the anterior and posterior of the disk, he hopes to identify differences in expression of proteins involved in the inflammatory cascade that may help explain why symptomatic disk degeneration occurs and the relationship between disk degeneration and sensory neurons.
Pain may be the only enemy
“The front of the disk is sparsely innervated, usually doesn’t have herniations, and usually isn’t painful,” said Dr. Kepler, “The back is where all the action happens.” By geographically mapping the inflammatory cascade within the disk, he hopes to isolate the molecules that are responsible for causing pain. “Degeneration is the enemy only because in some people, it causes symptoms. The real enemy is pain.”
His goal is to develop treatment strategies that are clinically relevant and, eventually, to design a way to block the action of a protein associated with pain in the disk. “That might include a treatment that would block protein receptors or key intermediaries associated with disk degeneration, perhaps even at a disk-specific level,” he said. “We want to identify disks that are painful and deliver treatment there—something nonsurgical that would make people with painful degeneration feel more like people with painless degeneration. We are not aiming to eliminate degeneration but rather the associated symptoms.” Although still at pre-clinical stages, his laboratory has recently shown suppression of the inflammatory cascade by blocking the protein receptor of a key intermediary in the transmission of diskogenic pain.
Ongoing research is essential
As for how he’s been aided by his OREF grant, Dr. Kepler said, “Business as usual in medicine just isn’t a good strategy. It’s essential that we deepen our understanding of orthopaedic disease and develop new treatment protocols. OREF is one of the organizations that pushes the field forward.” He believes that one of OREF’s great strengths is providing support for people who are interested in research to talk and interact. “No one lab can expand the whole body of knowledge,” he explained. “It takes too much time and too much money. You have to do research collaboratively, and this is what OREF makes possible.” 1
United States Bone and Joint Initiative: The Burden of Musculoskeletal Diseases in the United States
, Second Edition. Rosemont, IL; American Academy of Orthopaedic Surgeons; 2011.