Kappa Delta Young Investigator focused on treating IVD at molecular level

Madeleine Lovette & Terry Stanton

Intervertebral disk (IVD) degeneration leading to chronic back pain is a common musculoskeletal condition that affects millions of people worldwide. Current treatment options—both surgical and nonsurgical—focus on easing the symptoms of IVD degeneration. But Xudong Joshua Li, MD, PhD, an assistant professor in the department of orthopaedic surgery at the University of Virginia, Charlottesville, wanted to find out if a way could be found to address the pathologic processes that occur early in the course of the disease. His studies on “Growth and Differentiation Factor-5 (GDF-5) Modulation in Intervertebral Disc Degeneration” earned him the 2012 Young Investigator Kappa Delta Award.

“An effective biologic-based therapy that alters the course of degenerative disk disease is needed,” Dr. Li continued. “GDF-5 could be a potential therapeutic agent for early and moderate disk degeneration in future clinical applications.”

Attacking IVD early
Traditionally, disk degeneration has been considered largely a biomechanic phenomenon. However, it is now believed to result from complex interactions of biologic and biomechanic factors. The precise etiology and pathophysiology of IVD disease remain to be clearly delineated. It is known that the matrix of a healthy nucleus pulposus is rich in proteoglycans and type II collagen, whereas the annulus fibrosus is rich in type I collagen.

“One significant characteristic of the early stages of IVD disease is the progressive decline in proteoglycan,” Dr. Li said. “One of the main strategies for therapy involves increasing the synthesis of certain extracellular matrix components.”

Reduced proteoglycan content can have consequences for the disk’s ability to resist mechanical loads. “The ability to restore proteoglycan content may therefore be of therapeutic benefit, by increasing disk hydration and improving biomechanics,” Dr. Li said.

During the past 7 years, Dr. Li and his colleagues have performed a series of studies to investigate the effects of GDF-5 on different phases of the disease via gene- and cell-based experimental approaches.

“The insights into the role of GDF-5 in the skeleton have developed significantly since its discovery in 1994. GDF-5 has been found to be key in assuring normal development and formation of bone, joints, tendons, and ligaments,” said Dr. Li. “In particular, GDF-5 has been found directing the cartilage formation. Our studies found that GDF-5 deficiency leads to early IVD changes.”

Other findings include the following:

• GDF-5 gene therapy could effectively stimulate matrix metabolism of intervertebral disk cells in vitro.
• GDF-5 gene therapy could promote the healing of degenerated intervertebral disks.
• Tissue engineering, in combination with GDF-5–engineered stem cells, is worth further investigation.

Different treatment strategies
“Different stages of disk degeneration deserve different treatment strategies,” explained Dr. Li. “In the early stages of disk degeneration, the nucleus pulposus still has abundant cells, making non–cell-based treatment, such as in vivo gene transfer or growth factor injection, the most suitable strategy for minimally invasive treatment.”

As IVD degeneration progresses, however, functional nucleus pulposus cells disappear, so that for the moderate disk degeneration, an ex vivo approach is better. In the end stages of degeneration, the disk may be virtually nonexistent, replaced by a thin mass of fibrous tissue. At that point, a tissue-engineered or artificial disk will be needed, believes Dr. Li.

“We found that the deficiency of GDF-5, an important growth factor for chondrogenesis, would lead to early IVD change,” Dr. Li said. “Our results also showed that GDF-5 gene therapy could effectively stimulate matrix metabolism of intervertebral disk cells in vitro. GDF-5 may be a good candidate to potentiate intervertebral disk regeneration by enhancing the number of viable cells and/or their rate of matrix synthesis.”

Dr. Li reports no commercial affiliations. He received research grants from the AO Foundation, the Scoliosis Research Foundation, the North American Spine Society, the Musculoskeletal Transplant Foundation, and the National Institutes of Health.

Madeleine Lovette is the communications specialist in the AAOS office of government relations and can be reached at lovette@aaos.org

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

Bottom Line

• Current treatment options for intervertebral disk (IVD) degeneration focus on treating symptoms, rather than on preventing or delaying the course of the disease.
• Because both biologic and biomechanic factors contribute to the development of IVD degeneration, biologic-based genetic therapy could be potentially therapeutic.
• Growth and differentiation factor-5 (GDF-5) is necessary for the normal development of joints.
• By stimulating the matrix metabolism of intervertebral disk cells, GDF-5 gene therapy could promote the healing of degenerated intervertebral disks.