Low back pain (LBP), as a leading cause of disability, is a common musculoskeletal disorder that results in major social and economic burdens. Recent research has identified inflammation and related signaling pathways as important factors in the onset and progression of disc degeneration, a significant contributor to LBP. Inflammatory mediators also play an indispensable role in discogenic LBP. The suppression of LBP is a primary goal of clinical practice but has not received enough attention in disc research studies. Here, an overview of the advances in inflammation-related pain in disc degeneration is provided, with a discussion on the role of inflammation in IVD degeneration and pain induction. Puncture models, mechanical models, and spontaneous models as the main animal models to study painful disc degeneration are discussed, and the underlying signaling pathways are summarized. Furthermore, potential drug candidates, either under laboratory investigation or undergoing clinical trials, to suppress discogenic LBP by eliminating inflammation are explored. We hope to attract more research interest to address inflammation and pain in IDD and contribute to promoting more translational research.

Intervertebral disk (IVD) degeneration is a natural progression of the aging process. Degenerative disk disease (DDD) is a pathologic condition associated with IVD that has been associated with chronic back pain. There are a variety of different mechanisms of DDD (genetic, mechanical, exposure). Each of these pathways leads to a final common result of unbalancing the anabolic and catabolic environment of the extracellular matrix in favor of catabolism. Attempts have been made to gain an understanding of the process of IVD degeneration with in Vitro studies. These models help our understanding of the disease process, but are limited as they do not come close to replicating the complexities that exist with an in Vivo model. Animal models have been developed to help us gain further understanding of the degenerative cascade of IVD degeneration In Vivo and test experimental treatment modalities to either prevent or reverse the process of DDD. Many modalities for treatment of DDD have been developed including therapeutic protein injections, stem cell injections, gene therapy, and tissue engineering. These interventions have had promising outcomes in animal models. Several of these modalities have been attempted in human trials, with early outcomes having promising results. Further, increasing our understanding of the degenerative process is essential to the development of new therapeutic interventions and the optimization of existing treatment protocols. Despite limited data, biological therapies are a promising treatment modality for DDD that could impact our future management of low back pain.

Advanced age is the greatest risk factor for the majority of human ailments, including spine‐related chronic disability and back pain, which stem from age‐associated intervertebral disc degeneration (IDD). Given the rapid global rise in the aging population, understanding the biology of intervertebral disc aging in order to develop effective therapeutic interventions to combat the adverse effects of aging on disc health is now imperative. Fortunately, recent advances in aging research have begun to shed light on the basic biological process of aging. Here we review some of these insights and organize the complex process of disc aging into three different phases to guide research efforts to understand the biology of disc aging. The objective of this review is to provide an overview of the current knowledge and the recent progress made to elucidate specific molecular mechanisms underlying disc aging. In particular, studies over the last few years have uncovered cellular senescence and genomic instability as important drivers of disc aging. Supporting evidence comes from DNA repair‐deficient animal models that show increased disc cellular senescence and accelerated disc aging. Additionally, stress‐induced senescent cells have now been well documented to secrete catabolic factors, which can negatively impact the physiology of neighboring cells and ECM. These along with other molecular drivers of aging are reviewed in depth to shed crucial insights into the underlying mechanisms of age‐related disc degeneration. We also highlight molecular targets for novel therapies and emerging candidate therapeutics that may mitigate age‐associated IDD. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1289–1306, 2016.

Study Design. A review of the literature on macromechanical factors that accelerate disc degeneration with particular focus on distinguishing the roles of immobilization and overloading. Objective. This review examines evidence from the literature in the areas of biomechanics, epidemiology, animal models, and intervertebral disc physiology. The purpose is to examine: 1) what are the degeneration-related alterations in structural, material, and failure properties in the disc; and 2) evidence in the literature for causal relationships between mechanical loading and alterations in those structural and material properties that constitute disc degeneration. Summary of Background Data. It is widely assumed that the mechanical environment of the intervertebral disc at least in part determines its rate of degeneration. However, there are two plausible and contrasting theories as to the mechanical conditions that promote degeneration: 1) mechanical overload; and 2) reduced motion and loading. Results. There are a greater number of studies addressing the “wear and tear” theory than the immobilization theory. Evidence is accumulating to support the notion that there is a “safe window” of tissue mechanical conditions in which the discs remain healthy. Conclusions. It is concluded that probably any abnormal loading conditions (including overload and immobilization) can produce tissue trauma and/or adaptive changes that may result in disc degeneration. Adverse mechanical conditions can be due to external forces, or may result from impaired neuromuscular control of the paraspinal and abdominal muscles. Future studies will need to evaluate additional unquantified interactions between biomechanics and factors such as genetics and behavioral responses to pain and disability.

A new technique to measure the viscoelastic behavior of the nucleus pulposus in shear was used to assess its solid and fluid characteristics. To review existing knowledge on mechanical behaviors of the nucleus pulposus, and to develop a new technique to study the viscoelastic behaviors of isolated nucleus pulposus samples in torsional (pure) shear under transient and dynamic conditions. Numerous studies have investigated the swelling behavior of the nucleus and found the swelling pressure to range approximately 0.05-3 MPa, depending on loading conditions. Very few studies, however, have investigated the load-deformational behaviors of the nucleus pulposus. Thirteen nondegenerate samples of nucleus pulposus were harvested from lumbar discs and tested in torsional shear under transient and dynamic test conditions. A linear viscoelastic law with variable amplitude relaxation spectrum was used to model the stress relaxation and dynamic frequency sweep experiments. The coefficients of the viscoelastic law were determined from the stress relaxation experiments, whereas the dynamic shear modulus and phase shift angle were determined from the frequency sweep. The nucleus exhibits significant viscoelastic effects in shear. Under transient conditions, the stress relaxed to values near zero, which is indicative of the “fluid-like” behaviors of the nucleus. Under dynamic conditions, however, the material parameters for the nucleus, magnitude of the complex modulus (7-21 kPa), and phase angle (23-31°) were more characteristic of a viscoelastic solid. The authors' proposed stress-strain law exhibited excellent agreement with the viscoelastic data. In response to shear deformations, the nucleus pulposus exhibited significant viscoelastic effects, characteristic of a fluid and a solid. Whether the nucleus pulposus behaves more as a fluid or a solid in vivo depends on the rate of loading.