The Role of Hypoxia in Angiogenesis and Extracellular Matrix Regulation of Intervertebral Disc Cells During Inflammatory Reactions

Kwon, Woo Keun; Moon, Hong Joo; Kwon, Taek Hyun; Park, Youn Kwan; Kim, Joo Han

doi:10.1093/neuros/nyx149

Cited by 65 publications

(53 citation statements)

References 28 publications

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“…Low back pain is an enormous medical and socioeconomic burden in modern society. Although there are many etiologies for the development of low back pain, a main component appears to be IVD degeneration, including neovascularization and inflammatory element (Cornejo, Cho, Giannarelli, Iatridis, & Purmessur, ; Freemont et al, ; Kwon, Moon, Kwon, Park, & Kim, ; Risbud & Shapiro, ). In the present study, we demonstrate the important role of Tnmd in prevention of IVD degeneration by maintaining the avascular nature of the IVD (Figure j).…”

Section: Discussionmentioning

confidence: 99%

“…AF, annulus fibrous; EP, endplate; H&E, hematoxylin-eosin; IAF, inner annulus fibrous; IVD, intervertebral disc; NP, nucleus pulposus; OAF, outer annulus fibrous; WT, wild-type; black arrows, chondrocyte-like cells; white arrows, ectopic ossifications; white dotted line, OAF-IAF boundary. Scale bar: 200 μm (Cornejo, Cho, Giannarelli, Iatridis, & Purmessur, 2015;Freemont et al, 1997;Kwon, Moon, Kwon, Park, & Kim, 2017;Risbud & Shapiro, 2014). In the present study, we demonstrate the important role of Tnmd in prevention of IVD degeneration by maintaining the avascular nature of the IVD (Figure 6j).…”

Section: Human Umbilical Vein Endothelial Cells Migrate More Towardmentioning

confidence: 99%

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Loss of tenomodulin expression is a risk factor for age‐related intervertebral disc degeneration

et al. 2020

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The intervertebral disc (IVD) degeneration is thought to be closely related to ingrowth of new blood vessels. However, the impact of anti‐angiogenic factors in the maintenance of IVD avascularity remains unknown. Tenomodulin (Tnmd) is a tendon/ligament‐specific marker and anti‐angiogenic factor with abundant expression in the IVD. It is still unclear whether Tnmd contributes to the maintenance of IVD homeostasis, acting to inhibit vascular ingrowth into this normally avascular tissue. Herein, we investigated whether IVD degeneration could be induced spontaneously by the absence of Tnmd. Our results showed that Tnmd was expressed in an age‐dependent manner primarily in the outer annulus fibrous (OAF) and it was downregulated at 6 months of age corresponding to the early IVD degeneration stage in mice. Tnmd knockout (Tnmd−/−) mice exhibited more rapid progression of age‐related IVD degeneration. These signs include smaller collagen fibril diameter, markedly lower compressive stiffness, reduced multiple IVD‐ and tendon/ligament‐related gene expression, induced angiogenesis, and macrophage infiltration in OAF, as well as more hypertrophic‐like chondrocytes in the nucleus pulposus. In addition, Tnmd and chondromodulin I (Chm1, the only homologous gene to Tnmd) double knockout (Tnmd−/−Chm1−/−) mice displayed not only accelerated IVD degeneration, but also ectopic bone formation of IVD. Lastly, the absence of Tnmd in OAF‐derived cells promoted p65 and matrix metalloproteinases upregulation, and increased migratory capacity of human umbilical vein endothelial cells. In sum, our data provide clear evidences that Tnmd acts as an angiogenic inhibitor in the IVD homeostasis and protects against age‐related IVD degeneration. Targeting Tnmd may represent a novel therapeutic strategy for attenuating age‐related IVD degeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Human Umbilical Vein Endothelial Cells Migrate More Towardmentioning

confidence: 99%

Loss of tenomodulin expression is a risk factor for age‐related intervertebral disc degeneration

et al. 2020

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“…Most of them have been successfully used to activate Notch signaling in NP [21,22]. In addition, HIF-1α expression was significantly increased in the IL-1β-stimulated NP cells under hypoxic condition [23]. We therefore speculate that the overexpressed inflammatory factors participate in consistent activation of the Notch and HIF-1α pathways and subsequent initiation of IVD degeneration in MCs patients, especially MC I and MC II on MRI [24].…”

Section: Discussionmentioning

confidence: 99%

Interaction Between HIF-1α and Notch Signaling Pathways in Nucleus Pulposus Cells of Patients with Modic Changes

Xiong¹,

Guo²,

Jian³

et al. 2020

Preprint

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Background The HIF-1α/Notch signaling pathway has been shown to regulate proliferation, apoptosis, and metabolism in the intervertebral disc (IVD). The NP is an important structure adjacent to the disc. However, the roles of HIF1α and Notch signaling pathways in NP cells of patients with different Modic changes (MCs) are unclear. The purpose of this research was to assess the expression and association of HIF-1α and components of the Notch pathway in nucleus pulposus (NP) tissue of patients with various MCs. Methods Eighty-five surgical NP tissue samples were obtained from patients undergoing microdiscectomy procedures for the treatment of low back and root pain caused by prolapse of the IVD. The NP tissues were divided into four groups based on the adjacent endplate degeneration: MC I, II, III, and negative MC groups. The expression of HIF-1α and Notch-related components were measured and compared. Results The expression of HIF-1α, Notch1, and Notch2 were gradually increased in the MC I and MC II groups compared with that of the negative MC group. Meanwhile, HIF-1α and Notch-related components were rarely detected in MC III group. Conclusions The expression of HIF-1α/Notch is increased in the NP cells of patients with MC I and MC II. Application of the association between HIF-1α/Notch signaling pathway could be promising target for clinical diagnosis and treatment of disc degeneration in MC patients. Zekang Xiong and Jun Ding contributed equally to this work. Affiliations

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“…The level of the cartilage oligomeric matrix protein (COMP) (3,8), an extracellular matrix protein thatis involved in intervertebral disc catabolic metabolism, was also determined. In addition to these markers, the levels of matrix metalloproteinase (MMP)-7 and MMP-19 (16,23,24) and interleukin (IL)-1β (10), the main proinflammatory cytokine of the intervertebral disc, were examined using the quantitative reverse transcriptase realtime polymerase chain reaction (qRT-PCR).…”

Section: Original Investigationmentioning

confidence: 99%

Investigation of the effects of methylphenidate, an amphetamine derivative, on intervertebral disc tissue cell cultures and matrix structures

Kaya

Karaarslan²,

Şirin³

et al. 2019

Turkish Neurosurgery

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AIM: To investigate the effects of methylphenidate (MPH), on intervertebral disc tissue (IVD) cell cultures and extracellular matrix structures. Changes in the expression of some important marker genes involved in anabolic and catabolic mechanisms of IVD extracellular matrix formation were also evaluated. MATERIAL and METHODS: Primary cultures of nucleus pulposus cells (NPCs) and annulus fibrosus cells (AFCs) were isolated from tissues obtained from the operated patients. Cell viability and proliferation were tested, and the cell surface morphologies were evaluated by microscopy. The expressions of the chondroadherin (CHAD), cartilage oligomeric matrix protein (COMP), interleukin-1 beta (IL-1β) and matrix metalloproteinase (MMP)-7 and MMP-19 genes were evaluated using the quantitative real-time polymerase chain reaction (qRT-PCR). A value of p<0.05 was considered statistically significant. RESULTS: The viability and proliferation of intervertebral disc tissue cells decreased in response to MPH treatment and the expression of the investigated genes also changed. CONCLUSION: The data obtained from in-vitro studies may not directly adaptable to clinical applications. However, the fact that the central nervous system stimulant MPH can suppress proliferation of cells derived from IVD tissue should be considered carefully by clinicians.

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The Role of Hypoxia in Angiogenesis and Extracellular Matrix Regulation of Intervertebral Disc Cells During Inflammatory Reactions

Abstract: We found that hypoxia can enhance the angiogenic ability of IVD during inflammatory reactions, and cause progress in development of DDD via extracellular matrix regulation in this in vitro study.

Cited by 65 publications

References 28 publications

Loss of tenomodulin expression is a risk factor for age‐related intervertebral disc degeneration

Loss of tenomodulin expression is a risk factor for age‐related intervertebral disc degeneration

Interaction Between HIF-1α and Notch Signaling Pathways in Nucleus Pulposus Cells of Patients with Modic Changes

Investigation of the effects of methylphenidate, an amphetamine derivative, on intervertebral disc tissue cell cultures and matrix structures

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