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

Krock E, Rosenzweig DH, Chabot-Doré AJ, Jarzem P, Weber MH, Ouellet JA, Stone LS, Haglund L - J. Cell. Mol. Med. (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Orthopeadic Research Laboratory, Division of Orthopedic Surgery, McGill University, Montreal, QC, Canada; McGill Scoliosis and Spine Research Group, Montreal, QC, Canada.

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Comparison of factors released by healthy, pain-free and degenerating, painful intervertebral disc (IVDs) measured by protein arrays. The mean relative quantity of each factor released by healthy pain-free IVDs (grey bars) and degenerating, painful IVDs (black bars) are presented (A–D). Factors in blue have not been previously associated with disc degeneration or pain (A), factors in red have been associated with pain, but not disc degeneration (B), factors in black have been associated with disc degeneration (C) and factors in purple have been associated with both disc degeneration and pain (D). (E) Mean relative quantities of select factors involved in nociception are plotted to show individual variation between donors. n = 8 in degenerating, painful group and n = 11 in healthy, pain-free group, SEM for A–D, ±95% CI for E, unpaired t-test. *P < 0.05, **P < 0.01, ***P < 0.001.
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fig05: Comparison of factors released by healthy, pain-free and degenerating, painful intervertebral disc (IVDs) measured by protein arrays. The mean relative quantity of each factor released by healthy pain-free IVDs (grey bars) and degenerating, painful IVDs (black bars) are presented (A–D). Factors in blue have not been previously associated with disc degeneration or pain (A), factors in red have been associated with pain, but not disc degeneration (B), factors in black have been associated with disc degeneration (C) and factors in purple have been associated with both disc degeneration and pain (D). (E) Mean relative quantities of select factors involved in nociception are plotted to show individual variation between donors. n = 8 in degenerating, painful group and n = 11 in healthy, pain-free group, SEM for A–D, ±95% CI for E, unpaired t-test. *P < 0.05, **P < 0.01, ***P < 0.001.

Mentions: Although the degenerating IVD media induced neurite growth, the same concentration range of NGF alone was insufficient. Therefore, protein arrays were used to identify potential cooperative factors [30]. Degenerating and painful IVDs released significantly higher levels of 20 of these factors (Fig.5A-D, Table1). Fifteen factors had a P value below 0.01 (GCSF, GM-CSF, IFN-γ, IL-2, IL-3, IL-5, IL-6, IL-7, IL-15, CCL2, CCL7, CCL8, MIG, RANTES and TNF-β), and five factors had a P value between 0.01 and 0.05 (IL-1α, IL-13, TNF-α, GRO and CXCL1). There was no difference in the relative quantities of IL-8, IL-10 and TGF-β1 between the two groups (Fig.5D, Table1). The relative mean quantities and a summary of previous studies implicating specific factors with either degenerating IVDs and/or pain are listed in Table1. Of particular interest are IFN-γ, IL-6, CCL2 and CXCL1 because of their suggested role in IVD degeneration, neuronal sensitization and pain [10,31–37]. Figure5E shows the individual donor variation in these factors. IFN-γ and CXCL1 showed a fairly large donor variation especially in the degenerate samples whereas the levels of IL-6 and CCL2 were much more homogeneous in their expression levels within each of the two groups.


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

Krock E, Rosenzweig DH, Chabot-Doré AJ, Jarzem P, Weber MH, Ouellet JA, Stone LS, Haglund L - J. Cell. Mol. Med. (2014)

Comparison of factors released by healthy, pain-free and degenerating, painful intervertebral disc (IVDs) measured by protein arrays. The mean relative quantity of each factor released by healthy pain-free IVDs (grey bars) and degenerating, painful IVDs (black bars) are presented (A–D). Factors in blue have not been previously associated with disc degeneration or pain (A), factors in red have been associated with pain, but not disc degeneration (B), factors in black have been associated with disc degeneration (C) and factors in purple have been associated with both disc degeneration and pain (D). (E) Mean relative quantities of select factors involved in nociception are plotted to show individual variation between donors. n = 8 in degenerating, painful group and n = 11 in healthy, pain-free group, SEM for A–D, ±95% CI for E, unpaired t-test. *P < 0.05, **P < 0.01, ***P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4508160&req=5

fig05: Comparison of factors released by healthy, pain-free and degenerating, painful intervertebral disc (IVDs) measured by protein arrays. The mean relative quantity of each factor released by healthy pain-free IVDs (grey bars) and degenerating, painful IVDs (black bars) are presented (A–D). Factors in blue have not been previously associated with disc degeneration or pain (A), factors in red have been associated with pain, but not disc degeneration (B), factors in black have been associated with disc degeneration (C) and factors in purple have been associated with both disc degeneration and pain (D). (E) Mean relative quantities of select factors involved in nociception are plotted to show individual variation between donors. n = 8 in degenerating, painful group and n = 11 in healthy, pain-free group, SEM for A–D, ±95% CI for E, unpaired t-test. *P < 0.05, **P < 0.01, ***P < 0.001.
Mentions: Although the degenerating IVD media induced neurite growth, the same concentration range of NGF alone was insufficient. Therefore, protein arrays were used to identify potential cooperative factors [30]. Degenerating and painful IVDs released significantly higher levels of 20 of these factors (Fig.5A-D, Table1). Fifteen factors had a P value below 0.01 (GCSF, GM-CSF, IFN-γ, IL-2, IL-3, IL-5, IL-6, IL-7, IL-15, CCL2, CCL7, CCL8, MIG, RANTES and TNF-β), and five factors had a P value between 0.01 and 0.05 (IL-1α, IL-13, TNF-α, GRO and CXCL1). There was no difference in the relative quantities of IL-8, IL-10 and TGF-β1 between the two groups (Fig.5D, Table1). The relative mean quantities and a summary of previous studies implicating specific factors with either degenerating IVDs and/or pain are listed in Table1. Of particular interest are IFN-γ, IL-6, CCL2 and CXCL1 because of their suggested role in IVD degeneration, neuronal sensitization and pain [10,31–37]. Figure5E shows the individual donor variation in these factors. IFN-γ and CXCL1 showed a fairly large donor variation especially in the degenerate samples whereas the levels of IL-6 and CCL2 were much more homogeneous in their expression levels within each of the two groups.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Orthopeadic Research Laboratory, Division of Orthopedic Surgery, McGill University, Montreal, QC, Canada; McGill Scoliosis and Spine Research Group, Montreal, QC, Canada.

Show MeSH
Related in: MedlinePlus