The lifetime adult prevalence rate for low back pain has been estimated at between 50 and 80% with a point prevalence rate from 15–30%. The variation in prevalence rates have been attributed to differences in type and frequency of surveillance conducted.1
The management of individuals with chronic low back pain (LBP) is as varied as the supposed underlying causes, yet no one intervention has been shown to be superior to another.2;3
This leaves LBP as a largely unmet healthcare need. Given the lack of evidence-based medicine to manage LBP, it is imperative that basic research be performed to better elucidate the molecular mechanisms responsible for this condition. However, progress in this field has been stalled by our inability to track the molecular underpinnings associated with chronic degenerative changes in the spine over time in a human population. While tissue samples are available at the time of surgical intervention, the collection of such samples throughout the progression of the degeneration would be detrimental to the patient and therefore untenable. The advancement of MRI technology has made longitudinal studies of those individuals with chronic LBP possible, but the inferred knowledge gained through MRI is not sufficient to understand specific molecular changes. Bone marrow edema (BME) observed on MRI,4
is associated with chronic LBP and has been commonly referred to by specific “Modic changes.”5;6
The Modic type 1 change (MT1), defined as decreased signal intensity on T1 weighted images and increased signal intensity on T2 weighted images, has been shown to be associated with an inflammatory response in the bone marrow and degeneration of the endplate,5–7
and has been positively correlated with discogenic pain.8;9
Modic type 2 changes (MT2), defined as increased signal intensity on T1 weighted images and either isointensity or slight increase in intensity on T2 weighted images, have been shown to be associated with the return of fatty marrow and decreased pain.6;7
The set of cellular and molecular conditions that leads to the MT2 type change is largely unknown, thus a greater understanding of the recovery process could ultimately lead to a more pointed and effective intervention strategy.
Ankylosing Spondylitis (ASp) is a chronic, inflammatory disease that is characterized by sacroilitis, inflammatory back pain, restricted spinal mobility, peripheral arthritis, spondylitis, and enthsitis.10;11
Recent treatments of rheumatic diseases, such as ASp, have attempted to disrupt the signaling pathway of a critical cytokine, tumor necrosis factor (TNF), involved in the inflammatory immune response. Development of novel therapeutic agents such as infliximab, etanercept, and adalimumab that bind to TNF rendering it unable to fulfill its role as the apex of the inflammatory signaling pathway, have proven effective in treating inflammatory disease states. It has been shown that this class of drugs is effective in treating both the symptoms of ASp and the inflammation associated with the disease.12
Moreover, BME observed on contrast enhanced (CE)-MRI in affected vertebrae of ASp patients has been validated as a true biomarker of painful disease, as it correlates with disease severity and amelioration with anti-TNF therapy,13
and it also is predictive of a patient’s ability to return to work.14
Additionally, histology of retrieval tissue obtained from ASp patients has confirmed the vascular and cellular changes in the bone marrow of affected vertebrae to be the nature of the CE-MRI signals.15
Thus, while the etiology of ASp is largely different from that of chronic LBP and degenerative disc disease (DDD), the potential role of anti-TNF therapy and the utility of BME as a biomarker in the later, beg further investigation.
Preliminary results involving off-label use of anti-TNF therapy in cases of LBP involving radicular pain and sciatica associated with DDD and disc herniation have had varying success, depending on inclusion criteria, and the route of delivery.16–21
Perispinal and epidural injections of anti-TNF drugs have been reported to have immediate and long lasting positive effects,16;22
delivery of such drugs have had mixed results. Most recently, multicenter, randomized, double-blind, placebo-controlled trial of adalimumab in 265 patients with severe and acute sciatica demonstrated that a short course of subcutaneous anti-TNF therapy resulted in a small effect on leg pain and in significantly fewer surgical procedures.17
Remarkably, there have been no preclinical studies to date that have attempted to assess the efficacy of anti-TNF therapy for DDD and its potential mechanism of action for this condition.
For many diseases, animal models play an important role in clarifying pathogenesis and testing new and existing interventions. In the era of translational research, the mouse has emerged as an invaluable animal model based on its remarkable genomic conservation with human, transgenic technology, the availability of molecular probes, and cost effectiveness (money, time, labor). However, the generation of a lumbar spine model in the mouse has been prohibitive due to the highly invasive surgery required; whose side effects often involve paralysis and death. In recognition of this, the rodent tail has evolved as a surrogate model, despite its significant differences from the lumbar spine.23
Recently, we have expanded this animal modeling to murine caudal vertebrae. We have shown using contrast enhanced MRI (CE-MRI) and corresponding histology to track the progression of DDD and the development of bone marrow edema in both wild type (WT) and TNF-Tg mice a correlation between the MRI signal intensity and the cellular and vascular density in both the chronically compressed WT mice and immune compromised TNF-Tg mice.24
Based on these results and the potential of anti-TNF therapy for DDD, we tested the hypotheses that: 1) TNF is necessary for the induction of chronic compression-induced BME, and 2) compression-induced BME is ameliorated by release of the load and TNF inhibition.