Intervertebral disc degeneration and how it leads to low back pain

Abstract

The purpose of this review was to evaluate data generated by animal models of intervertebral disc (IVD) degeneration published in the last decade and show how this has made invaluable contributions to the identification of molecular events occurring in and contributing to pain generation. IVD degeneration and associated spinal pain is a complex multifactorial process, its complexity poses difficulties in the selection of the most appropriate therapeutic target to focus on of many potential candidates in the formulation of strategies to alleviate pain perception and to effect disc repair and regeneration and the prevention of associated neuropathic and nociceptive pain. Nerve ingrowth and increased numbers of nociceptors and mechanoreceptors in the degenerate IVD are mechanically stimulated in the biomechanically incompetent abnormally loaded degenerate IVD leading to increased generation of low back pain. Maintenance of a healthy IVD is, thus, an important preventative measure that warrants further investigation to preclude the generation of low back pain. Recent studies with growth and differentiation factor 6 in IVD puncture and multi‐level IVD degeneration models and a rat xenograft radiculopathy pain model have shown it has considerable potential in the prevention of further deterioration in degenerate IVDs, has regenerative properties that promote recovery of normal IVD architectural functional organization and inhibits the generation of inflammatory mediators that lead to disc degeneration and the generation of low back pain. Human clinical trials are warranted and eagerly anticipated with this compound to assess its efficacy in the treatment of IVD degeneration and the prevention of the generation of low back pain.

Comprehensive narrative review on the analysis of outcomes from cell transplantation clinical trials for discogenic low back pain

“…The previous also underlines the likely misguided focus of cell therapy solely on the NP. Additional strategies for AF and endplate repair, or combined approaches, will likely be beneficial for specific LBP conditions and warrants further investigation [101] . Similarly, alternative strategies to intradiscal injection that could introduce the beneficial (effects of) cells into the disc can potentially reduce the dependency on the deteriorated IVD integrity [ 23 , 102 ].…”

An update on animal models of intervertebral disc degeneration and low back pain: Exploring the potential of artificial intelligence to improve research analysis and development of prospective therapeutics

“… 212 Paraspinal muscles affected by IVDD are major pain centers in the spine. 212 A rat multifidus transection model of IVDD shows the inter‐dependance of spinal muscles and the IVD. 213 This is a useful model which utilizes an intact IVD and shows how induction of spinal instability can initiate IVDD without violating IVD structure directly.…”

“…The altered biomechanical loading on the degenerate IVD and mechanical destabilization alters cell‐ECM signaling resulting in the production of inflammatory cytokines and active MMPs which further promotes disc degenerative process. 212 Degenerative changes in the disc ECM conducive to neovascularization and the ingrowth of nerves and an elevation in the production of inflammatory cytokines and neurotrophic factors all lead to a significant deterioration in the normal cellular microenvironment in the IVD resulting in increased numbers of mechano‐and nociceptive pain receptors. 214 Noxious stimuli in the IVD such as an acidic pH, ECM degeneration, inflammatory mediators and neurotrophins generate inflammatory conditions in the IVD that promote this increase in noci‐ and mechanoreceptors.…”

“…Animal models have provided invaluable information of molecular events occurring during IVDD, and importantly have demonstrated how changes in the IVD microenvironment can lead to the development of discogenic LBP and pain in other spinal structures such as muscle, CEP, facet joint and spinal ligaments 212 . Paraspinal muscles affected by IVDD are major pain centers in the spine 212 . A rat multifidus transection model of IVDD shows the inter‐dependance of spinal muscles and the IVD 213 .…”

“…This is a useful model which utilizes an intact IVD and shows how induction of spinal instability can initiate IVDD without violating IVD structure directly. The altered biomechanical loading on the degenerate IVD and mechanical destabilization alters cell‐ECM signaling resulting in the production of inflammatory cytokines and active MMPs which further promotes disc degenerative process 212 . Degenerative changes in the disc ECM conducive to neovascularization and the ingrowth of nerves and an elevation in the production of inflammatory cytokines and neurotrophic factors all lead to a significant deterioration in the normal cellular microenvironment in the IVD resulting in increased numbers of mechano‐and nociceptive pain receptors 214 .…”