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Intervertebral disc degeneration and its involvement in a modern day epidemic

Estimations suggest that at least 80% of adult individuals suffer from low back pain at some point in their lives and many of them are chronically disabled by this condition. The socio-economic costs associated with low back pain are enormous reaching up to $90 billion in the USA in annual costs to alleviate and treat the pain. The degeneration of the intervertebral disc (IVD) is thought to be the primary contributor to low back pain causing the compression of the spinal nerves and adjacent vertebrae. The exact causes leading to IVD degeneration are yet to be fully clarified but aging, excessive physical labor and genetic factors are thought to be the three main factors associated with the degenerative process. Current treatments to alleviate pain include rest, exercise and administration of analgesic and anti-inflammatory drugs. When these treatments are ineffective, patients need to undergo surgical interventions like spinal fusion or artificial disc replacement.

The IVD is a soft tissue between the vertebrae that functions as shock absorber and lends stability as well as flexibility to the spine. IVD is composed of three distinct components: 1) the nucleus pulposos (NP), the gelatinous inner core of the disc that primarily bears the pressure; 2) the annulus fibrosus (AF), the outer portion of the disc that consists of several layers (laminae) of fibrocartilage; and 3) the vertebral end plate (VEP), composed of fibrocartilage that surrounds the disc and separates the IVD from the spinal vertebrae. The majority of the tissue present in the IVD is composed of extracellular matrix (ECM). It is characterized by a high concentration of negatively-charged proteoglycans (PG), which increase the water content in the NP and confer its gelatinous aspect. Proteoglycans, together with other molecules like semaphorins, also provide an unfavorable environment for neurite and blood vessel growth, thus causing IVD to be the largest aneural and avascular tissue within the human body.

IVD degeneration appears to be a multistep process. Following initial insult (e.g. mechanical trauma, infection or genetic predisposition), IVD cells upregulate the expression of pro-inflammatory cytokines, particularly IL-1β and TNF-α. These cytokines are known for their potent ability to increase the production of ECM-degrading enzymes including matrix metalloproteinases (MMPs). These enzymes promote degradation of predominant ECM molecules such as proteoglycans and collagen type II. The subsequent structural breakdown of ECM in IVD results in mechanical spinal instability leading to annular tears, disc herniation and possibly spinal stenosis. Although the majority of adults have some form of structural degeneration of one or more IVDs, this process is not always accompanied by pain. Pain generation is therefore an event secondary to the structural IVD deficit. Evidences suggest that discogenic pain is characterized by neurite ingrowth into an otherwise aneural IVD.

In their recent work, Dr. Krock and colleagues from the McGill University in Montreal, investigated the factors actively released by degenerating and painful IVDs and whether they can directly induce innervations and activation of pain-sensing fibers. They used an ex vivo approach by surgically removing whole IVDs from patients or organ donors. This approach left the IVD cells in their native environment, minimized the effect of cell isolation and culture, and maintained in vivo cell density. Amongst the factors identified in IVD-conditioned media, degenerating IVDs from patients with chronic low back pain released significantly higher levels of TNF-α, nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) compared to healthy discs as quantified by ELISA. Moreover, media from degenerating and painful IVD was found to stimulate neurite growth in neuronal cell lines. Treatment with an anti-NGF antibody was sufficient to reduce neurite sprouting. Surprisingly, the concentration of NGF found in degenerating IVD media was relatively low (44.2 ± 6.5pg/ml). When NGF was added to neuronal cell cultures at similar concentration to the one measured in degenerating IVD conditioned media, neurite sprouting was not induced. This data suggests that other factors released by degenerating IVDs are required in addition to NGF to induce neurite sprouting. In addition, using Enzo’s polyclonal antibody against calcitonin gene-related peptide (CGRP), the authors also demonstrated that degenerating, painful IVDs secrete a combination of factors that increase CGRP expression in neurons, a well known neurotransmitter strongly associated with pain. Amongst the 23 different cytokines analyzed, of particular interest is the up-regulation of IFN-γ, IL-6, CCL2 and CXCL1 because of their involvement in nociception, the development of chronic neuronal sensitization, hyper-excitability and chronic pain. Interestingly, inhibition of NGF also blocked CGRP expression suggesting a central role of NGF in both neo-innervation and pain in vivo. Based on these findings, further development of anti-NGF therapies should be envisaged for the treatment of IVD-related low back pain.

Enzo Life Sciences offers a comprehensive product portfolio for advancing your research in neuroscience and inflammation including antibodies, ELISA kits, and small molecules; some of which are listed below:

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Reference:

  1. E. Krock, et al. Painful, degenerating intervertebral discs up-regulate neurite sprouting and CGRP through nociceptive factors. J. Cell. Mol. Med. (2014) 18:1213.
  2. M.V Risbud and I.M Shapiro. Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat. Rev. Rheumatol. (2014) 10:44.

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