Nucleus Pulposus Cells Upregulate PI3K/Akt and MEK/ERK Signaling Pathways Under Hypoxic Conditions and Resist Apoptosis Induced by Serum Withdrawal

Risbud, Makarand V.; Fertala, Jolanta; Vresilovic, Edward J.; Albert, Todd J.; Shapiro, Irving M.

doi:10.1097/01.brs.0000159096.11248.6d

Cited by 125 publications

(118 citation statements)

References 29 publications

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“…However, only limited studies have appeared until now reporting the activation and/or the function of these pathways in IVD cells or tissues [34][35][36]. Accordingly, we have studied the activation of the MEK/ ERK and the PI 3-K/Akt pathways in bovine IVD cells in response to PDGF, bFGF and IGF-I.…”

Section: Discussionmentioning

confidence: 99%

PDGF, bFGF and IGF-I stimulate the proliferation of intervertebral disc cells in vitro via the activation of the ERK and Akt signaling pathways

2007

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Intervertebral disc (IVD) degeneration is frequently characterized by increased cell proliferation, probably as a tissue regenerative response. Although many growth factors and their receptors have been shown to be expressed normally in the disc, and generally to be overexpressed during degeneration, not all of them have been thoroughly studied concerning their effects on IVD cell proliferation. In the present report, three potent mitogens, platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF) and insulin-like growth factor-I (IGF-I) are examined regarding their capacity to induce proliferation in vitro of bovine coccygeal nucleus pulposus (NP) and annulus fibrosus (AF) cells, as well as to activate major intracellular signal transduction pathways. PDGF, bFGF and IGF-I were found to induce DNA synthesis in quiescent IVD cells in a dose-dependent manner. Maximum stimulation was induced by PDGF, while stimulation by all three factors simultaneously exceeded only slightly that caused by PDGF alone. All three growth factors were shown to phosphorylate immediately extracellular-signal regulated kinases (ERKs), while the stimulation by bFGF especially resulted in sustained ERK phosphorylation. Furthermore, all three growth factors induced phosphorylation of Akt in both Thr308 and Ser473 residues immediately after stimulation, although bFGF-induced phosphorylation was much weaker than that provoked by PDGF and IGF-I. In addition, the MEK inhibitor PD98059 and the PI 3-K inhibitor wortmannin were shown to block growth factor-induced ERK-and Akt-phosphorylation, respectively, in IVD cells. Inhibition of the MEK/ERK or the PI 3-K/Akt pathways provoked a significant decline of the proliferative effects of PDGF, bFGF or IGF-I on IVD cell cultures, while the simultaneous inhibition of both signaling pathways abolished completely the mitogenicity of these growth factors. The above effects of the three growth factors were reproduced similarly in both NP and AF cell cultures. Overall, the above results indicate that PDGF, bFGF and IGF-I stimulate the proliferation of IVD cells via the ERK and Akt signaling pathways.

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Section: Discussionmentioning

confidence: 99%

PDGF, bFGF and IGF-I stimulate the proliferation of intervertebral disc cells in vitro via the activation of the ERK and Akt signaling pathways

2007

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“…They also demonstrated that galectin 3 has a prosurvival role in the intervertebral disc (7). Moreover, Risbud and colleagues showed that hypoxia confers protection against apoptosis via the PI3K/Akt and MAPK pathways in nucleus pulposus cells (8). More recently, as discussed by Gogate et al (9), hypoxia was shown to regulate expression of ␤-1,3-glucuronyltransferase 1 nucleus, a key enzyme in glycosaminoglycan synthesis in nucleus pulposus cells.…”

Section: To the Editormentioning

confidence: 97%

“…Nucleus pulposus cells generate energy through anaerobic glycolysis rather than through oxidative phosphorylation (4); thus, it is not surprising that a hypoxia-regulated pathway plays an important role in nucleus pulposus cell survival. In fact, a number of recent studies also demonstrated that hypoxia regulates nucleus pulposus survival via other signaling molecules, including vascular endothelial growth factor (VEGF) (5,6), galectin 3 (7), phosphatidylinositol 3-kinase [PI3K]/Akt, and MAPK (8), in a hypoxia-inducible factor (HIF)-independent manner. Indeed, a study by Fujita and colleagues has shown that VEGF and its receptors are expressed by nucleus cells in hypoxia and that this protein promotes nucleus pulposus survival (5).…”

Section: To the Editormentioning

confidence: 99%

New evidence of the role of the hypoxia‐regulated pathway in nucleus pulposus cell survival: Comment on the article by Hiyama et al

Yuan

Wang

Cao

et al. 2012

Arthritis & Rheumatism

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“…In addition, an important consideration is the harsh microenvironment within the degenerated intervertebral disc, which is characterised by reduced oxygen (Grunhagen et al, 2006) and reduced glucose concentration, (Bibby et al, 2005) creating a challenge in maintaining viable cellular populations (Antoniou et al, 1996). For chondrocytes, tissue specific oxygen gradients have been shown to play an important role in maintaining tissue phenotype through the hypoxia inducible factor (HIF) family of nuclear regulatory elements (Malda et al, 2003) in a similar manner to TGF-β supplementation through MEK/ERK and PI3k/Akt pathways (Pratsinis et al, 2012;Risbud et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

In vitro extracellular matrix accumulation of nasal and articular chondrocytes for intervertebral disc repair

Vedicherla

Buckley

2017

Tissue and Cell

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Chondrocyte based regenerative therapies for intervertebral disc repair such as Autologous Disc Cell Transplantation (ADCT, CODON) and allogeneic juvenile chondrocyte implantation (NuQu®, ISTO Technologies) have demonstrated good outcomes in clinical trials. However concerns remain with the supply demand reconciliation and issues surrounding immunoreactivity which exist for allogeneic-type technologies. The use of stem cells is challenging due to high growth factor requirements, regulatory barriers and differentiation towards a stable phenotype. Therefore, there is a need to identify alternative non-disc cell sources for the development and clinical translation of next generation therapies for IVD regeneration. In this study, we compared Nasal Chondrocytes (NC) as a non-disc alternative chondrocyte source with Articular Chondrocytes (AC) in terms of cell yield, morphology, proliferation kinetics and ability to produce key extracellular matrix components under 5% and 20% oxygen conditions, with and without exogenous TGF-β supplementation.Results indicated that NC maintained proliferative capacity with high amounts of sGAG and lower collagen accumulation in the absence of TGF-β supplementation under 5% oxygen conditions. Importantly, osteogenesis and calcification was inhibited for NC when cultured in IVD-like microenvironmental conditions. The present study provides a rationale for the exploration of nasal chondrocytes as a promising, potent and clinically feasible autologous cell source for putative IVD repair strategies.

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Nucleus Pulposus Cells Upregulate PI3K/Akt and MEK/ERK Signaling Pathways Under Hypoxic Conditions and Resist Apoptosis Induced by Serum Withdrawal

Abstract: It is concluded that under hypoxic conditions, rat nucleus pulposus cells are adapted for survival by regulation of expression of critical genes, downregulation of apoptosis through activation of the PI3K/Akt and MAPK survival pathways.

Cited by 125 publications

References 29 publications

PDGF, bFGF and IGF-I stimulate the proliferation of intervertebral disc cells in vitro via the activation of the ERK and Akt signaling pathways

PDGF, bFGF and IGF-I stimulate the proliferation of intervertebral disc cells in vitro via the activation of the ERK and Akt signaling pathways

New evidence of the role of the hypoxia‐regulated pathway in nucleus pulposus cell survival: Comment on the article by Hiyama et al

In vitro extracellular matrix accumulation of nasal and articular chondrocytes for intervertebral disc repair

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