Vascular endothelial growth factor (VEGF)‐induced angiogenesis in herniated disc resorption

Haro, Hirotaka; Kato, Tsuyoshi; Komori, Hiromichi; Osada, Motonobu; Shinomiya, Kenichi

doi:10.1016/s0736-0266(01)00150-4

Cited by 131 publications

(127 citation statements)

References 27 publications

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“…It is difficult to reconcile this information with direct measurements of VEGF levels in the nucleus pulposus. A review of the pertinent literature indicates that there is no information on VEGF levels in the normal avascular disc; although not directly related to this investigation, it is known that VEGF, VEGF receptor 1 (VEGFR-1), and VEGFR-2 are expressed in herniated discs and discs that are forming granulation tissue (33).…”

Section: Discussionmentioning

confidence: 95%

Cited2 modulates hypoxia‐inducible factor–dependent expression of vascular endothelial growth factor in nucleus pulposus cells of the rat intervertebral disc

Agrawal¹,

Gajghate²,

Smith³

et al. 2008

Arthritis & Rheumatism

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Objective. To determine whether nucleus pulposus cells of the intervertebral disc express hypoxiainducible factor 2␣ (HIF-2␣), and to assess the role of HIF-1 and HIF-2 in controlling cited2 and vascular endothelial growth factor (VEGF) expression.Methods. Rat cells were cultured under normoxic (21% O 2 ) or hypoxic (2% O 2 ) conditions, and expression and promoter activity of HIF-2 target genes were evaluated. Gain-or loss-of-function experiments were performed to investigate the contribution of HIF isoforms to cited2 activity as well as the role of cited2 in regulating VEGF expression.Results. We found that HIF-2␣ protein was expressed in vivo and that protein and messenger RNA expression were similar under both normoxic and hypoxic conditions. However, there was a significant increase in HIF-2␣ transactivation under hypoxic conditions. With respect to functional activity, unlike the case in most other tissues, HIF-2 failed to increase the transcriptional activities of superoxide dismutase 2 and frataxin, 2 common target genes involved in radical dismutation. However, under hypoxic conditions, HIF-2 preferentially regulated the expression and promoter activity of cited2, a p300 binding protein. When HIF-2␣ or HIF-1␣ was suppressed, cited2 promoter activity was inhibited. Finally, we showed that forced expression or suppression of cited2 resulted in corresponding changes in expression of VEGF, a common target gene for HIF-1 and HIF-2 in the nucleus pulposus cells.Conclusion. Results of this study indicate that in nucleus pulposus cells, HIF-2 and HIF-1 modulate their own transcriptional activity through cited2. We suggest that the 2 arms of the regulatory circuit serve to maintain survival activities and inhibit angiogenesis in the healthy disc.

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Section: Discussionmentioning

confidence: 95%

Cited2 modulates hypoxia‐inducible factor–dependent expression of vascular endothelial growth factor in nucleus pulposus cells of the rat intervertebral disc

Agrawal¹,

Gajghate²,

Smith³

et al. 2008

Arthritis & Rheumatism

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“…5 Importantly, monocyte chemoattractant protein (MCP-1), a prototype of CC chemokine that contributes to the activation and recruitment of macrophages, 6 has been shown to be produced by IVD cells of the nucleus pulposus and annulus fibrosus 7 In addition, administration of MCP-1 in a rat autologous transplantation model of IVD results in a reduction in the size of the implanted disc. 8 Thus MCP-1 derived from IVD cells may play a critical role in natural HD resorption by triggering macrophage infiltration into HD tissue.…”

mentioning

confidence: 99%

“…TNF-a induced VEGF through the NF-kB pathway, which resulted in neovascularization of disc tissues. 5,15 The level of angiogenic activity in disc tissues was closely related to aging. 15 MCP-1 and MMPs play crucial roles in HD resorption.…”

mentioning

confidence: 99%

Age‐related expression of MCP‐1 and MMP‐3 in mouse intervertebral disc in relation to TWEAK and TNF‐α stimulation

Fujita

Ando

Ohba

et al. 2011

Journal Orthopaedic Research

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This study was undertaken to investigate the age-related differences of monocyte chemotactic protein-1 (MCP-1) and matrix metalloproteinase-3 (MMP-3) expression in mouse intervertebral disc (IVD) and to determine whether MMP-3 plays a role in disc degeneration. Expression of MCP-1 and MMP-3 mRNA in mouse IVD was assessed by quantitative PCR. The ability of MCP-1 and MMP-3 expression in IVD to respond to TNF-a or TWEAK stimulation was examined by quantitative PCR, WB, ELISA, and immunohistochemistry. IVD derived from MMP-3-deficient and wild-type mice were compared using Safranin-O staining and immunohistochemistry. mRNA levels of MCP-1 and MMP-3 in IVD significantly diminished and the ability of MCP-1 or MMP-3 expression to respond to TNF-a or TWEAK stimulation was significantly reduced as age increased. IVD derived from 64-week-old wild-type mice showed clearly diffuse proteoglycan loss by Safranin-O staining and immunohistochemistry compared with younger mice. However, no loss of proteoglycan and typeII collagen were observed in IVD derived from 64-week-old MMP-3-deficient mice. MCP-1 and MMP-3 expression in mouse IVD showed age-related decreases. The response to inflammation in IVD also displayed age-related changes. Therefore, disc degeneration may vary with the patients' age and targeting MMP-3 may be a possible future therapeutic strategy for disc degeneration. ß

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“…4,5 TNF-a stimulates matrix metalloproteinase (MMP)-3 in the disc in an autocrine/paracrine manner, causing further infiltration of Mj and degeneration of extracellular matrix. [4][5][6] However, the resorption mechanism has not been clarified.We previously revealed that nonthermal low-intensity pulsed ultrasound (LIPUS) stimulation was effective for enhancing resorption, and accelerating the rate of disc degeneration. 7 LIPUS therapy promotes bone fracture healing in human subjects, 8 modulates gene expression in osteoblasts or chondrocytes, 9,10 and influences second messenger activities related to angiogenesis.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Role of the tumor necrosis factor‐α, cyclooxygenase‐2, prostaglandin E2, and effect of low‐intensity pulsed ultrasound in an in vitro herniated disc resorption model

Iwabuchi¹,

Ito²,

Chikanishi³

et al. 2008

Journal Orthopaedic Research

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Spontaneous herniated disc resorption occurs via inflammatory reactions involving abundant neovascularization and macrophage phagocytotic activity. Nonthermal low-intensity pulsed ultrasound (LIPUS) treatment might be effective in shortening the duration of disc resorption. We developed a rat in vitro resorption model in which a coccygeal intervertebral disc and peritoneal macrophages were cocultured. Secretion of tumor necrosis factor-a (TNF-a) from macrophages was promoted by LIPUS, and the process of disc degeneration was thus accelerated. In this study, we further examined the effects of LIPUS using this in vitro model focusing on whether LIPUS affects cyclooxygenase-2 (COX-2) signaling pathways. We found that the levels of COX-2 and prostaglandin E2 (PGE2) secreted from macrophages were increased by LIPUS. However, these phenomena were not caused by LIPUS directly, as the levels of these substances were reduced by neutralizing TNF-a activity. Moreover, the wet weights of the disc samples were not changed by addition of PGE2, but were reduced by recombinant TNF-a. Our results suggest that the effects of LIPUS in enhancing the process of herniated disc resorption are caused mainly by TNF-a. Keywords: low-intensity pulsed ultrasound; herniated disc; TNF-a; COX-2; PGE2A herniated disc (HD) is defined as a degenerated intervertebral disc protruding toward the spinal canal. Mechanical compression by an HD and chemical stimulation with substances such as tumor necrosis factor-a (TNF-a) can be potential causes of radiculopathy. 1 Pain may be relieved by surgical removal of the ruptured disc. Recently, spontaneous resorption of exposed HDs was recognized by magnetic resonance imaging (MRI), 2 and conservative treatments are now often selected to relieve pain. 3 The mechanism of HD resorption may involve inflammatory reactions correlated with abundant neovascularization and macrophage (Mj) phagocytotic activity. 4,5 TNF-a stimulates matrix metalloproteinase (MMP)-3 in the disc in an autocrine/paracrine manner, causing further infiltration of Mj and degeneration of extracellular matrix. [4][5][6] However, the resorption mechanism has not been clarified.We previously revealed that nonthermal low-intensity pulsed ultrasound (LIPUS) stimulation was effective for enhancing resorption, and accelerating the rate of disc degeneration. 7 LIPUS therapy promotes bone fracture healing in human subjects, 8 modulates gene expression in osteoblasts or chondrocytes, 9,10 and influences second messenger activities related to angiogenesis. We hypothesized that LIPUS stimulation would promote inflammatory activity, and therefore we examined the effects of LIPUS on a rat HD resorption model involving coculture of coccygeal ID tissues and peritoneal Mj. The LIPUS exposure enhanced TNF-a secretion by Mj, and disc wet weights were decreased by stimulation after 4 days of culture. 7 These results suggested that LIPUS activates the infiltration of Mj into cocultured disc samples, thus accelerating resorption.Cyclooxygenase-2 (COX-2...

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Vascular endothelial growth factor (VEGF)‐induced angiogenesis in herniated disc resorption

Cited by 131 publications

References 27 publications

Cited2 modulates hypoxia‐inducible factor–dependent expression of vascular endothelial growth factor in nucleus pulposus cells of the rat intervertebral disc

Cited2 modulates hypoxia‐inducible factor–dependent expression of vascular endothelial growth factor in nucleus pulposus cells of the rat intervertebral disc

Age‐related expression of MCP‐1 and MMP‐3 in mouse intervertebral disc in relation to TWEAK and TNF‐α stimulation

Role of the tumor necrosis factor‐α, cyclooxygenase‐2, prostaglandin E2, and effect of low‐intensity pulsed ultrasound in an in vitro herniated disc resorption model

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