JAAOS article reviews current science, therapies

Intervertebral disk (IVD) degeneration is a complex process that was recognized as a clinical entity before the underlying molecular pathophysiology was studied or understood. Research into the molecular basis of degenerative disk disease has greatly increased understanding of the biology underlying this complex process. In the September issue of the Journal of the AAOS (JAAOS), Christopher K. Kepler, MD, and colleagues examined the current state of knowledge about the disease process and reviewed emerging and available biologic treatments.

They noted that much is still unknown; what is known is that the degenerative cascade not only disrupts normal extracellular matrix (ECM) protein synthesis but also increases production of inflammatory cytokines and degradative enzymes. These molecular degenerative pathways may offer targets for therapeutic intervention to slow or reverse disk degeneration. Potential biologic options for the management of IVD degeneration include disk cell reimplantation, stem cell implantation, disk denervation, protein injection, and gene therapy.

Dr. Kepler and senior author D. Greg Anderson, MD, elaborated on their review of this promising field of study in a question-and-answer session with AAOS Now.

AAOS Now: In learning about or exploring emerging biologic treatments, what do we need to know about IVD anatomy and biomechanics?

Dr. Kepler: The anatomy of the IVD is important because its two main components, the nucleus pulposus (NP) and the annulus fibrosus (AF), have very different biomechanical functions and each has a distinct pattern of degeneration from a morphologic perspective. The NP loses water content over time, which reduces its capacity to absorb compressive loads, resulting in the transfer of stresses to other structures such as the facet joints. In contrast, the healthy AF can resist tensile stresses; it is the loss of its structural integrity that allows herniation of the NP normally contained within the AF.

AAOS Now: What is relevant to know about the molecular basis of IVD degeneration?

Dr. Anderson: It is important to understand how the normal anabolic and catabolic processes in the IVD are altered in tissue degradation leading to disk degeneration. Although environmental factors have traditionally been blamed for the onset of disk degeneration, the current literature suggests that as much as 70 percent of an individual’s susceptibility is genetically related.

Many degradative molecules play a role in the degenerative process, making it difficult to identify specific targets for intervention. In addition, numerous signaling molecules alter the expression profile of disk cells, leading to the synthesis and release of catabolic enzymes and inflammatory cytokines, which modulate the breakdown process. Molecular strategies to achieve disk repair are based on the hypothesis that introducing the appropriate signaling molecules or environmental cues will alter that profile.

AAOS Now: What is cellular senescence and how does it relate to the discussion?

Dr. Kepler: Cellular senescence is the time when a cell stops dividing. Although senescent cells remain metabolically active, they cannot repopulate disks that have lost cells due to necrosis or apoptosis, which indirectly contributes to the declining cellularity seen in degenerative disks. Fewer cells means less ability to repair and maintain the extracellular matrix, likely leading to accelerated IVD degeneration.

AAOS Now: What are some of the challenging biochemical characteristics of the degenerative IVD?

Dr. Anderson: Many of the unique biochemical characteristics of the IVD also pose substantial challenges to potential therapies to repair or reverse disk degeneration. For example, the relative anoxic and avascular environment of the IVD makes it difficult for transplanted cells to survive. Similarly, the introduction of cells into the disk places an additional nutritional stress on an already constrained system. Given these factors, it’s surprising that animal models show cell survival and improved metabolic activity for several proposed repair strategies.

AAOS Now: How far along are the following potential treatment strategies in terms of clinical applications—disk cell reimplantation, stem cell implantation, platelet-rich plasma (PRP), painful disk denervation, injection of therapeutic proteins, and gene therapy?

Dr. Kepler: Despite the theoretical barriers to the transplantation of cells into the IVD, disk cell reimplantation is probably closest to achieving clinical use outside of research studies. A current prospective study (the “Euro Disc”) is examining the use of harvested, cultured, and reintroduced NP tissue. Although initial reports are promising, comprehensive descriptions of the study methodology and outcomes have not yet been released, pending completion of the trial; close scrutiny is warranted before this technique is considered suitable for more widespread clinical adoption.

The use of mesenchymal stem cells (MSCs) for disk regeneration faces similar challenges. Although this strategy has been explored in animals with mixed results, the use of stem cells for disk regeneration has not been studied systematically in humans and should be considered experimental until more solid data are available to support this approach. Some researchers have found it difficult to maintain stem cell transplants within the disk in a larger animal model (Göttingen minipigs), perhaps due to insufficient nutritional support within the IVD.

The rationale for using PRP in disk regeneration centers around the fact that PRP contains concentrated growth factors that might stimulate existing IVD cells to increase matrix production. Unfortunately, animal models provide little evidence that this treatment has a beneficial effect and no systemic studies reporting its effectiveness in humans have been published.

As for the use of either intradiscal electrothermic therapy (IDET) or intradiscal radiofrequency thermocoagulation (IRFT) to denervate painful disks, supporting evidence is poor. The best available evidence suggests that these procedures have little clinical benefit when compared with sham procedures.

A logical solution to decreased extracellular matrix production in the IVD is to stimulate the remaining cells to produce more matrix. However, such a strategy must take into account the complex balance of growth factors and degradative enzymes that promote matrix production and breakdown, respectively.

Animal studies have investigated the effect of a single intradiscal injection of various growth factors on disk height and extracellular matrix composition. The results were promising enough to motivate human trials using bone morphogenetic protein-7 (BMP-7) and growth and differentiation factor-5 (GDF-5). These two trials are ongoing and have not yet reported outcome data.

Gene therapy for symptomatic disk degeneration has yet to be tested in humans and does not appear likely in the near future. Concerns over the safety of viral vectors used to deliver the gene sequences and the inefficiency of other methods of gene delivery have only allowed use of this technology in small rodent studies.

AAOS Now: What challenges do researchers face?

Dr. Anderson: For preclinical studies, the lack of large animal models of spontaneous disk degeneration that might mimic the human situation is a challenge. Another challenge is the unique biomechanical environment of the human spine, given our upright posture.

Addressing the gaps in our understanding of why most degenerative disks are painless while a few are associated with disabling back pain is a challenge. Finally, much remains to be learned regarding the molecular basis of pain in the setting of degenerative changes within the disk. This is currently an area of active research.

AAOS Now: What are the clinical takeaways for both spine and other orthopaedic surgeons?

Dr. Kepler: We need to understand the molecular basis of the disease to guide our quest for better biologic therapies. Our growing understanding of the molecular mechanisms behind IVD homeostasis and the molecular events leading to disk degeneration is one example of how basic research may lead to potential new therapies for a difficult clinical problem. Although further investigation is necessary, human clinical trials have begun to explore reimplantation of autologous disk cells and the use of recombinant growth factors as potential treatment modalities for symptomatic disk degeneration.

Co-authors with Dr. Kepler and Dr. Anderson are Chadi Tannoury, MD, and Ravi K. Ponnappan, MD.

Disclosure information: Dr. Anderson—DePuy, Medtronic, Synthes, Seaspine, Globus Medical, Cervical Spine Research Society; Dr. Ponnappan—DePuy, Biomet. Drs. Kepler and Tannoury report no conflicts.

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

Bottom line:

• Ongoing research into the molecular basis of degenerative disk disease may identify biologic treatments to slow or reverse disk degeneration.
• Disk cell reimplantation, stem cell implantation, disk denervation, protein injection, and gene therapy are among the areas being studied.
• Human clinical trials are underway to explore reimplantation of autologous disk cells and the use of recombinant growth factors as potential treatment modalities.
• The lack of large animal models and an incomplete understanding of the molecular basis of pain in the setting of degenerative changes within the disk are among the challenges facing researchers.