Searching for new ways to treat IDD

Joon Yung Lee, MD; Nam Vo, PhD; and James D. Kang, MD, know they’ve fielded a real “dream team” at the University of Pittsburgh’s Ferguson Laboratory for Orthopaedic and Spine Research. Drs. Kang and Lee are spine surgeons at Ferguson, and Dr. Vo is working with them to research disk degeneration and the treatment of related health issues.

“Clinicians and basic scientists have invaluable and complementary insights to contribute to one another’s work,” noted Dr. Lee. “Basic scientists can keep your clinical thinking fresh and help steer you in promising new directions. But they can sometimes spin off on pretty deep tangents,” he added. “Clinicians can help keep them clinically grounded.”

“It’s a great yin-yang balance,” confirmed Dr. Vo.

Drs. Lee and Vo hit that synergistic sweet spot, when, at Dr. Kang’s urging, they applied as coprincipal investigators for a 2008 Orthopaedic Research and Education Foundation (OREF) grant to explore “A Novel Genetic Model of Accelerated Aging to Study the Cellular and Molecular Processes of Intervertebral Disk Aging.”

Their OREF-funded work, on which Dr. Kang collaborates, aims to demonstrate that a mouse model of premature aging fills an important unmet need in spine research. Mice may provide a predictable, reproducible living laboratory in which to identify key benchmarks of age-related intervertebral disk degeneration (IDD). The investigation focuses on identifying the genes and molecular changes involved in loss of disk matrix protein that occurs with aging.

The research encompasses well-studied matrix molecules—including aggrecan, versican, collagen I, and collagen II—and also aims to identify novel factors. A better understanding of this complex, dynamic molecular environment and how it changes with age may eventually point to new nonsurgical therapies to maintain disk integrity and biomechanics.

“We don’t really have a rapid, reproducible, and low-cost animal model for studying the natural history of age-related disk degeneration and testing potential nonsurgical management approaches,” said Dr. Lee. “Current models primarily involve disk trauma, which are useful for addressing questions regarding injury-induced disk degeneration. However, most clinical disk degeneration cases are age-related. As the proportion of mature adults grows in the next few decades, age-associated disk degeneration will only increase. A good aging model is essential,” he explained.

This project uses Ercc knockout mice, developed by the team’s University of Pittsburgh colleague Laura J. Niedernhofer, MD, PhD. The mice, which lack a gene critical in DNA repair, develop normally for the first 5 weeks, then show spontaneous and progressive signs of aging. Typically, they die before the age of 6 months—well before the usual 2- to 3-year life expectancy. The research team established microdissection of sesame seed-sized intervertebral disks from the mice and performed biochemical assays to analyze cell status and matrix composition of these disks at different ages.

New clinical options
IDD is part of the human condition—most disks show evidence of deterioration by the time people reach their 40s or 50s. It’s a major cause of back pain and need for spine surgery. Like other common conditions associated with aging, it accounts for significant national healthcare expenditures through procedure costs and lost productivity. Those costs will only increase as the population grows older.

Although treating IDD with spine surgery is often successful—and that level of success and patient gratitude bring both Drs. Lee and Kang a high level of professional satisfaction—it also has a potentially significant downside.

“I love to do surgery,” said Dr. Kang. “But it always carries risks. You can do a technically superb job, and patients can still have complications, including wound infections and paralysis.”

New nonsurgical management approaches could avoid those complications. Depending on potential targets identified, eventual nonsurgical alternatives could include treatment with medications, growth factors, gene therapy, or stem cells.

“A group of relatively young patients stands out for me among those who could benefit most from new medical management strategies,” said Dr. Lee. “These patients in their 40s, 50s, and 60s have excruciating pain and significant disability as a result of arthritis or other conditions characteristic of premature disk aging. One example is young moms who are in too much pain to lift their kids.

“We have to share with these patients the disheartening news that, as a group, their surgical outcomes are not what we’d like them to be. The chance of success is only about 60 percent. And ‘success’ means only about a 50 percent improvement in their symptoms,” he said.

OREF: A vital bridge
Dr. Kang’s own experience persuaded him to encourage Drs. Lee and Vo to apply for OREF funding.

“When I was in training in the late 1980s, I knew that I wanted to specialize in spine surgery, but I realized there wasn’t a great deal of science behind what spine surgeons did. I saw a huge opportunity for an academic spine surgeon to get involved in basic research,” Dr. Kang noted. “That’s the life that OREF champions.

“Now, as codirector of a multidisciplinary research lab, one major concern is job security for our young scientists and clinicians who are advancing our field in new directions. It’s pivotal that they learn to write proposals worthy of funding and gain early career experience in grantsmanship and the peer review process,” he continued.

The team has recently published the results of their work in the Journal of Orthopaedic Research. It is the first study of its kind demonstrating the use of DNA-repair-deficient mice as efficient and accurate models of age-associated disk degeneration.

Sally T. Halderman is a contributing writer for OREF and can be reached at communications@oref.org