Molecular therapy of the intervertebral disc

Yoon, Seung-Hwan; Patel, Nilpesh

doi:10.1007/s00586-006-0155-3

Cited by 79 publications

(60 citation statements)

References 68 publications

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“…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. Hence, we aimed at a systematic study of these three mitogens under the same experimental conditions.…”

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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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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“…Such approaches include the use of recombinant proteins, cytokines or growth factors [29], molecular therapy [58], gene transfer techniques [24,56], cell therapy [2,9]. These separate topics are so detailed that any attempt to summarise them in a few paragraphs would not do them justice.…”

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confidence: 99%

The vertebral endplate: disc degeneration, disc regeneration

2006

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The vertebral endplates are critical for maintaining disc function yet like other components of the disc are vulnerable to degeneration. This paper provides an overview of the development and normal function of the endplates as well as an impression of what happens when they undergo progressive degeneration. Recent research suggests that the degenerative process can be retarded or reversed.Keywords Disc AE Endplate AE Degeneration AE Regeneration ManuscriptDespite all that is known from decades of research the intervertebral disc remains an enigma. It is a unique and remarkable entity and perhaps the one aspect that is responsible for much of its mystery is that such a large structure is able to survive and function under the most difficult physiological conditions. The discs of the human spine are the largest non-vascularised structures in the body, and in the largest of them (in the lumbar spine) some cells can be 20 mm from the nearest direct blood supply. Despite their apparent resilience however, the resident cells are not immortal. It is not unusual for discs to show signs of deterioration by the age of 25 years and it is in this regard that the vertebral endplate plays an important role.Discs are roughly cylindrical structures that vary in size and shape progressively from the cervical to the lumbar region. They all comprise a well-hydrated central nucleus pulposus that is surrounded by the firm but flexible collagenous lamellae of the annulus fibrosus [40]. At the cranial and caudal ends of each disc are the endplates that separate the vertebral bone from the disc itself and prevent the highly hydrated nucleus from bulging into the adjacent vertebrae. The endplates also absorb the considerable hydrostatic pressure that results from mechanical loading of the spine [10]. The endplates are typically less than 1 mm thick, and while this varies considerably across the width of any single disc, they tend to be thinnest in the central region adjacent to the nucleus [16,44].The endplates are identifiable from an early embryological stage and have an osseous as well as a hyaline cartilage component [50]. The cartilaginous component appears to generate great interest since it persists throughout normal maturation while the adjacent vertebrae undergo ossification. It comprises a gel of hydrated proteoglycan molecules reinforced by a network of collagen fibrils. Unlike the articular cartilage of the synovial joints the collagen fibrils do not connect the endplate directly to the vertebral bone [22], although the endplate does have intimate contact with the disc through the lamellae of the inner annulus [21]. A network of microscopic blood vessels penetrates the endplates during development of the growing spine, principally to provide nutrition for the disc, before disappearing around the time of skeletal maturity [50]. Apart from a sparse vascular supply in the outer

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“…Disc degeneration has been suggested to be a phenomenon characterized by an imbalance between anabolism and catabolism of the matrix molecules [54]. Reduction in viable cell density has been associated with degeneration and aging.…”

Section: Changes In Disc Cells With Advancing Degenerationmentioning

confidence: 99%