Release of active and depot GDF-5 after adenovirus-mediated overexpression stimulates rabbit and human intervertebral disc cells

Wang, Haili; Kroeber, Markus; Hanke, Michael; Ries, Rainer; Schmid, Carsten; Poller, Wolfgang; Richter, Wiltrud

doi:10.1007/s00109-003-0507-y

Cited by 61 publications

(41 citation statements)

References 36 publications

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“…Consistent with previous reports, Ad-GDF-5 treatment not only promotes the expression of ECM proteins but also could improve the construction and function of NP cells in vivo via the sustained transcription and translation of ECM proteins (Wang et al, 2004;Feng et al, 2008;Liang et al, 2010).…”

Section: Discussionsupporting

confidence: 91%

“…Additionally, previous experiments suggest that GDF-5 can successfully induce collagen II and aggrecan gene expression in the IVD cells of GDF-5-deficient mice cultured in alginate beads (Li et al, 2004). GDF-5 protein or gene mediated by adenovirus can increase the main ECM, such as collagen and proteoglycan, to enhance the gene expression of collagen II and aggrecan (Wang et al, 2004;Cui et al, 2008). A single injection of Ad-GDF-5 into a degenerated mice disc has shown that the results not only confirmed the long-term expression of the target protein in the disc in vivo but also highlighted the physiological improvements that occurred to the disc (Williams et al, 2011).…”

Section: Discussionmentioning

confidence: 96%

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Adenovirus-mediated GDF-5 promotes the extracellular matrix expression in degenerative nucleus pulposus cells

Luo

Liu

Zhu

et al. 2016

J. Zhejiang Univ. Sci. B

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Abstract:Objective: To construct a recombinant adenovirus vector-carrying human growth and differentiation factor-5 (GDF-5) gene, investigate the biological effects of adenovirus-mediated GDF-5 (Ad-GDF-5) on extracellular matrix (ECM) expression in human degenerative disc nucleus pulposus (NP) cells, and explore a candidate gene therapy method for intervertebral disc degeneration (IDD). Methods: Human NP cells of a degenerative disc were isolated, cultured, and infected with Ad-GDF-5 using the AdEasy-1 adenovirus vector system. On Days 3, 7, 14, and 21, the contents of the sulfated glycosaminoglycan (sGAG), deoxyribonucleic acid (DNA) and hydroxyproline (Hyp), synthesis of proteoglycan and collagen II, gene expression of collagen II and aggrecan, and NP cell proliferation were assessed. Results: The adenovirus was an effective vehicle for gene delivery with prolonged expression of GDF-5. Biochemical analysis revealed increased sGAG and Hyp contents in human NP cells infected by Ad-GDF-5 whereas there was no conspicuous change in basal medium (BM) or Ad-green fluorescent protein (GFP) groups. Only cells in the Ad-GDF-5 group promoted the production of ECM, as demonstrated by the secretion of proteoglycan and up-regulation of collagen II and aggrecan at both protein and mRNA levels. The NP cell proliferation was significantly promoted. Conclusions: The data suggest that Ad-GDF-5 gene therapy is a potential treatment for IDD, which restores the functions of degenerative intervertebral disc through enhancing the ECM production of human NP cells.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 96%

Adenovirus-mediated GDF-5 promotes the extracellular matrix expression in degenerative nucleus pulposus cells

Luo

Liu

Zhu

et al. 2016

J. Zhejiang Univ. Sci. B

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“…Most of the studies, however, are focusing on the effect of growth factors on the production and/or degradation of ECM, and only some of them are dealing with growth factor-induced cell proliferation. For example, proliferation of IVD cells has been shown in response to BMP-2 [42], BMP-7 [48], GDF-5 [7] and TGF-b1 [13], all of them belonging to the TGF-bsuperfamily. Furthermore, regarding the effects of classical potent mitogens such as PDGF, bFGF and IGF-I [50] on the proliferation of IVD cells in vitro, in some cases the data are indirect [1,8] or contradictory (e.g., regarding the effects of IGF-I on annulus fibrosus cells [14,41]), possibly due to the variety of the assay systems used.…”

Section: Introductionmentioning

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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“…Thus, alternative approaches of GDF-5 administration have been proposed that can ensure that the effects of GDF-5 are sustained. Delivery of the GDF-5 gene was demonstrated to be an alternative method [122]. The GDF-5 gene was transferred into IVD cells using adenovirus or plasmid vectors, and GDF-5 protein production in the transfected IVD cells was confirmed.…”

Section: Alternative Approaches To Gdf-5 Administrationmentioning

confidence: 99%

Growth and Differentiation Factor-5 Contributes to the Structural and Functional Maintenance of the Intervertebral Disc

Feng

Liu

Yang

et al. 2015

Cell Physiol Biochem

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Intervertebral disc degeneration (IDD) is a widely recognized contributor to low back pain (LBP). The Prevention or reversal of IDD is a potential treatment for LBP. Unfortunately, current treatments for IDD are aimed at relieving symptoms rather than regenerating disc structure or function. Recently, the injection of growth factors and mesenchymal stem cell (MSC) transplantation have been shown to be promising biological therapies for IDD. Growth factors stimulate the proliferation of and matrix synthesis by intervertebral disc (IVD) cells, leading to the regeneration of degenerative discs. Growth factors, hypoxia and co-culture with nucleus pulposus (NP) cells induce MSCs to differentiate toward an NP-like phenotype, which can increase the number of functional cells in the IVD or enhance the function of endogenous disc cells to facilitate IVD regeneration. Therefore, the emerging roles of growth factors in IVD regeneration have piqued the interest of researchers. Growth factors including transforming growth factor-β (TGF-β), fibroblast growth factor (FGF), insulin-like growth factor-1 (IGF-1) and growth and differentiation factor-5 (GDF-5), among others, have been demonstrated to enhance anabolism in IVD cells and to induce NP-like differentiation of MSCs. However, the injection of TGF, IGF and FGF into human IVDs may induce unwanted blood vessel ingrowth, which accelerates the process of IDD, the injection of GDF-5 may not have the same effect. This finding suggests that GDF-5 is a preferable growth factor for use in IDD treatment compared with TGF, IGF and FGF. The GDF-5 gene is one of the few growth factor genes that have been found to be associated with IDD thus far; moreover, the GDF-5 gene defects lead to collagen and proteoglycan abnormalities in discs in mice, suggesting that GDF-5 contributes to the structural and functional maintenance of the IVD. This review is focused on the functions of GDF-5 in the IVD and on the association between GDF-5 and a genetic predisposition to IDD. The effects of GDF-5 on IVD regeneration and on MSC differentiation are also discussed. GDF-5 plays a crucial role in the pathogenesis of IDD and is a promising therapeutic agent for IDD. Additionally, stem cell transplantation has been shown to be a promising biological therapy for IDD.

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Release of active and depot GDF-5 after adenovirus-mediated overexpression stimulates rabbit and human intervertebral disc cells

Cited by 61 publications

References 36 publications

Adenovirus-mediated GDF-5 promotes the extracellular matrix expression in degenerative nucleus pulposus cells

Adenovirus-mediated GDF-5 promotes the extracellular matrix expression in degenerative nucleus pulposus cells

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

Growth and Differentiation Factor-5 Contributes to the Structural and Functional Maintenance of the Intervertebral Disc

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