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Painful, degenerating intervertebral discs up-regulate neurite sprouting and CGRP through nociceptive factors.

ABSTRACT: Intervertebral disc degeneration (IVD) can result in chronic low back pain, a common cause of morbidity and disability. Inflammation has been associated with IVD degeneration, however the relationship between inflammatory factors and chronic low back pain remains unclear. Furthermore, increased levels of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) are both associated with inflammation and chronic low back pain, but whether degenerating discs release sufficient concentrations of factors that induce nociceptor plasticity remains unclear. Degenerating IVDs from low back pain patients and healthy, painless IVDs from human organ donors were cultured ex vivo. Inflammatory and nociceptive factors released by IVDs into culture media were quantified by enzyme-linked immunosorbent assays and protein arrays. The ability of factors released to induce neurite growth and nociceptive neuropeptide production was investigated. Degenerating discs release increased levels of tumour necrosis factor-?, interleukin-1?, NGF and BDNF. Factors released by degenerating IVDs increased neurite growth and calcitonin gene-related peptide expression, both of which were blocked by anti-NGF treatment. Furthermore, protein arrays found increased levels of 20 inflammatory factors, many of which have nociceptive effects. Our results demonstrate that degenerating and painful human IVDs release increased levels of NGF, inflammatory and nociceptive factors ex vivo that induce neuronal plasticity and may actively diffuse to induce neo-innervation and pain in vivo.

SUBMITTER: Krock E

PROVIDER: S-EPMC4508160 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Painful, degenerating intervertebral discs up-regulate neurite sprouting and CGRP through nociceptive factors.

Krock Emerson E Rosenzweig Derek H DH Chabot-Doré Anne-Julie AJ Jarzem Peter P Weber Michael H MH Ouellet Jean A JA Stone Laura S LS Haglund Lisbet L

Journal of cellular and molecular medicine 20140320 6

Intervertebral disc degeneration (IVD) can result in chronic low back pain, a common cause of morbidity and disability. Inflammation has been associated with IVD degeneration, however the relationship between inflammatory factors and chronic low back pain remains unclear. Furthermore, increased levels of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) are both associated with inflammation and chronic low back pain, but whether degenerating discs release sufficient concentr ...[more]

PMID: 24650225

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Project description:Replacement of the intervertebral disc with a viable, tissue-engineered construct that mimics native tissue structure and function is an attractive alternative to fusion or mechanical arthroplasty for the treatment of disc pathology. While a number of engineered discs have been developed, the average size of these constructs remains a fraction of the size of human intervertebral discs. In this study, we fabricated medium (3 mm height × 10 mm diameter) and large (6 mm height × 20 mm diameter) sized disc-like angle ply structures (DAPS), encompassing size scales from the rabbit lumbar spine to the human cervical spine. Maturation of these engineered discs was evaluated over 15 weeks in culture by quantifying cell viability and metabolic activity, construct biochemical content, MRI T2 values, and mechanical properties. To assess the performance of the DAPS in the in vivo space, pre-cultured DAPS were implanted subcutaneously in athymic rats for 5 weeks. Our findings show that both sized DAPS matured functionally and compositionally during in vitro culture, as evidenced by increases in mechanical properties and biochemical content over time, yet large DAPS under-performed compared to medium DAPS. Subcutaneous implantation resulted in reductions in NP cell viability and GAG content at both size scales, with little effect on AF biochemistry or metabolic activity. These findings demonstrate that engineered discs at large size scales will mature during in vitro culture, however, future work will need to address the challenges of reduced cell viability and heterogeneous matrix distribution throughout the construct. STATEMENT OF SIGNIFICANCE:This work establishes, for the first time, tissue-engineered intervertebral discs for total disc replacement at large, clinically relevant length scales. Clinical translation of tissue-engineered discs will offer an alternative to mechanical disc arthroplasty and fusion procedures, and may contribute to a paradigm shift in the clinical care for patients with disc pathology and associated axial spine and neurogenic extremity pain.

Dataset Information

Painful, degenerating intervertebral discs up-regulate neurite sprouting and CGRP through nociceptive factors.

Publications

Painful, degenerating intervertebral discs up-regulate neurite sprouting and CGRP through nociceptive factors.

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