Interleukin‐1β induces angiogenesis and innervation in human intervertebral disc degeneration

Abstract

Degenerative disorders of the intervertebral discs (IVDs) are generally characterized by enhanced matrix degradation, angiogenesis, innervation, and increased expression of catabolic cytokines. In this study, we investigated the effects of inflammatory cytokines, IL-1␤, and TNF-␣, on the expression of an angiogenic factor, vascular endothelial growth factor (VEGF), and neurotrophic factors, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), in human IVD degeneration. IL-1␤ and TNF-␣ stimulated the gene expression of VEGF, NGF, and BDNF in nucleus pulposus (NP) cells isolated from patient tissues. Immunohistochemical results demonstrated a positive correlation between IL-1␤ and VEGF/NGF/BDNF expression in human IVD tissues. RNA expression analysis of patient tissues also identified positive correlations between VEGF and platelet endothelial cell adhesion molecule-1 (PECAM-1) and between NGF/BDNF and protein gene product 9.5 (PGP9.5). Our findings suggest that IL-1␤ is generated during IVD degeneration, which stimulates the expression of VEGF, NGF, and BDNF, resulting in angiogenesis and innervation. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J. Orthop. Res. 29: 265-269, 2011 Keywords: interleukin-1␤; vascular endothelial growth factor (VEGF); angiogenesis; innervation; intervertebral disc (IVD) Degenerative changes in intervertebral discs (IVDs) include increased expression of catabolic cytokines, decreased synthesis of normal IVD matrix and enhanced matrix degradation, and disc cell senescence and apoptosis.1-5 IVD degeneration results in the loss of hydrophilic matrix molecules leading to spinal instability and is the main cause of disc-related diseases, such as disc herniation and spinal stenosis. Normal lumbar IVD is avascular and aneural except for the outer third of the annulus fibrosus (AF). However, previous studies have described the ingrowth of nerves into the AF and nucleus pulposus (NP) of degenerated IVD 6,7 and these nerves were usually accompanied by microvascular blood vessels.8 Though, the mechanisms underlying nerve ingrowth and neovascularization are largely unknown.Neurotrophins play a role in the survival, growth, differentiation, and function of neurons.9 The neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have been detected in human IVD degeneration and have been implicated in the promotion of nerve ingrowth and generation of discogenic pain. 8,10,11 A histologic study examining degenerative IVD tissues from rats demonstrated that the major population of disc-innervating dorsal root ganglion neurons was the NGF-dependent neurons.

Molecular Basis of Intervertebral Disc Degeneration and Herniations: What Are the Important Translational Questions?

“…The young, healthy intervertebral disc is mainly avascular and aneural except for the outer one-third of the AF [56]. As aging occurs, disc matrix proteoglycan, a known inhibitor of vascular ingrowth, decreases and degenerative changes such as microfissures stimulate growth of innervated, vascularized granulation tissue, which propagates along fissures through the outer AF to the inner AF and NP [43,70]. The vascularized granulation tissue permits the migration of macrophages and mast cells into the area as well.…”

“…The vascularized granulation tissue permits the migration of macrophages and mast cells into the area as well. Collectively, the granulation tissue and the infiltrating cells express growth factors and proinflammatory cytokines, including fibroblast growth factor, transforming growth factor b1 (TGF-b1), interleukin (IL) 1b, and tumor necrosis factor a (TNF-a) [1,43,70].…”

The NLRP3/Caspase-1/Interleukin-1β Axis Is Active in Human Lumbar Cartilaginous Endplate Degeneration

“…The inflammatory cytokine interleukin-1b (IL-1b) is a common proinflammatory factor believed to be involved in osteoarthritis and intervertebral disc degeneration [2,3,[22][23][24]. IL-1b is first synthesized as an inactive precursor to pro-IL-1b, which requires cleavage of its aminoterminal region by caspase-1 to change into the secreted active form.…”

Prolyl Hydroxylase 3 (PHD3) Modulates Catabolic Effects of Tumor Necrosis Factor-α (TNF-α) on Cells of the Nucleus Pulposus through Co-activation of Nuclear Factor κB (NF-κB)/p65 Signaling

“…□ S This article contains supplemental cules aggrecan and collagen type II (9 -12). TNF-␣ and IL-1␤ stimulate production of NGF, BDNF, and VEGF, molecules associated with nerve ingrowth and angiogenesis by nucleus pulposus cells (13). Recent work has shown that both TNF-␣ and IL-1␤ promote NF-B signaling in the nucleus pulposus and control expression of syndecan4, a heparan sulfate proteoglycan involved in ADAMTS5/aggrecanase-2 activation (14).…”