Findings lead to approval for FDA trials

For more than a decade, Dr. An and his colleagues at Rush University Medical Center have pursued research addressing intervertebral disk degeneration, facet joint osteoarthritis, lumbar spinal stenosis, and degenerative lumbar spondylolisthesis. Their overall goal is to better understand intervertebral disk biology by focusing on the discovery and characterization of important molecules associated with intervertebral disk degeneration and testing compounds of possible therapeutic value.

Their paper, “Intervertebral Disk Repair or Regeneration by Growth Factor and/or Cytokine Inhibitor Protein Injection,” describes their major findings and the resulting implications for future research and clinical testing. The paper is the winner of the 2011 Kappa Delta Elizabeth Winston Lanier Award.

To study the biologic mechanisms of intervertebral disk degeneration, researchers examined tissue from patients undergoing back surgery as well as from cadavers. They demonstrated that the content of large proteoglycans such as aggrecan and versican decreases with aging and intervertebral disk degeneration, while the amount present of certain small proteoglycans, such as biglycan, increases. They also noted an association between pro-inflammatory cytokines, such as interleukin-1 and tumor necrosis factor-α, and degeneration. Thus, these molecules may be biomarkers of degeneration and could possibly be targeted for therapy.

The research group has developed in vitro intervertebral disk cell and organ culture models and in vivo animal models to study disk degeneration and repair. It has also tested possible therapeutic agents to assess their potential for matrix restoration. In a rabbit annular puncture model of intervertebral disk degeneration, injections of either bone morphogenetic protein (BMP)-7 or BMP-14 were found to be effective in restoring intervertebral disk height, magnetic resonance image signals of the disk, biochemical matrix content, and disk biomechanical properties.

Based on these findings, the U.S. Food and Drug Administration recently approved Investigational New Drug clinical trials of two proprietary versions of these compounds.

Several other biologic therapies, including gene therapy, cell therapy, and other molecules that enhance matrix production or block pro-inflammatory cytokines, also have potential. “Clinicians will likely utilize a combination of these tools in the treatment of symptomatic low back pain depending on the patient’s age and the severity of intervertebral disk degeneration,” the authors write. “Biomechanical markers may identify those patients whose pain is related to the intervertebral disk, and also help identify molecules that block pain in addition to restoring the intervertebral disk structural matrix.”

Coauthors of the paper are Koichi Masuda, MD, PhD; Gabriella Cs-Szabo, PhD; Yejia Zhang, MD, PhD; Anna Chee, PhD; Gunnar B. J. Andersson, MD, PhD;Hee-Jeong Im, PhD; and Eugene J. Thonar, PhD.

Disclosures: Dr. An—Articular Engineering, Baxter, Dupuy Spine, Life Spine, Smith & Nephew, Spinal Kinetics, Synthes, U & I Inc; Dr. Masuda—Halozyme, Johnson & Johnson, Medtronic, Nippon Zoki, Nuvasive; Dr. Andersson—Biomerix, Biomet, Crosstrees, Lippincott, Ouroboros, Spartec, Spinal Kinetic, Wolters Kluwer Health; the other authors reported no conflicts.

Terry Stanton is the senior science writer for AAOS Now. He can be reached at tstanton@aaos.org