Potential Use of Sox9 Gene Therapy for Intervertebral Degenerative Disc Disease

Paul, Ronjon; Haydon, Rex C.; Cheng, Hongwei; Ishikawa, Akira; Nenadovich, Nikola; Jiang, Wei; Zhou, Lan; Breyer, Benjamin N.; Feng, Tao; Gupta, Purnendu; He, Tong‐Chuan; Phillips, Frank M.

doi:10.1097/01.brs.0000058946.64222.92

Cited by 165 publications

(100 citation statements)

References 44 publications

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“…Although different markers have been suggested for NP cells in the last few years, no ideal single marker has been identified so far, thus leading to the conclusion that the expression of a set of genes needs to be analyzed, such as HIF-1 (hypoxia induced factor) (Rajpurohit et al, 2002), GLUT-1 (glucose transporter) (Rajpurohit et al, 2002), MMP2 (matrix metalloproteinase 2) (Rajpurohit et al, 2002), CD24 (glycosylphosphat-idylinositol-anchored cell surface protein) (Fujita et al, 2005) and Sox9 (Paul et al, 2003). Both HIF-1 and GLUT-1 are related to the NP metabolic activity.…”

Section: Discussionmentioning

confidence: 99%

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Cell-seeded polyurethane-fibrin structures – A possible system for intervertebral disc regeneration

Mauth

Bono²,

Haas³

et al. 2009

eCM

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Nowadays, intervertebral disc (IVD) degeneration is one of the principal causes of low back pain involving high expense within the health care system. The long-term goal is the development of a medical treatment modality focused on a more biological regeneration of the inner nucleus pulposus (NP). Hence, interest in the endoscopic implantation of an injectable material took center stage in the recent past. We report on the development of a novel polyurethane (PU) scaffold as a mechanically stable carrier system for the reimplantation of expanded autologous IVDderived cells (disc cells) to stimulate regenerative processes and restore the chondrocyte-like tissue within the NP. Primary human disc cells were seeded into newly developed PU spheroids which were subsequently encapsulated in fibrin hydrogel. The study aims to analyze adhesion properties, proliferation capacity and phenotypic characterization of these cells. Polymerase chain reaction was carried out to detect the expression of genes specifically expressed by native IVD cells. Biochemical analyses showed an increased DNA content, and a progressive enhancement of total collagen and glycosaminoglycans (GAG) was observed during cell culture. The results suggest the synthesis of an appropriate extracellular matrix as well as a stable mRNA expression of chondrogenic and/or NP specific markers. In conclusion, the data presented indicate an alternative medical approach to current treatment options of degenerated IVD tissue.

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Section: Discussionmentioning

confidence: 99%

“…Even more interesting is the expression of Sox9 in 3D cultures. Paul et al (2003) studied the potential use of a recombinant adenoviral vector expressing Sox9 in human disc cells among others. It was shown that the expression of the chondrocyte-specific transcription factor clearly stimulated collagen type II synthesis in vitro.…”

Section: Discussionmentioning

confidence: 99%

Cell-seeded polyurethane-fibrin structures – A possible system for intervertebral disc regeneration

Mauth

Bono²,

Haas³

et al. 2009

eCM

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“…A chondrogenic transcription factor Sox9 plays a major role in an increased level of chondrogenesis in the mouse (Akiyama 2011;Tew and Clegg 2011) in particular by activating co-expression with collagen type II (Ng et al 1997;Marshall and Harley 2000;Davies et al 2007). Various gene therapy approaches using viral methods to over-express Sox9 resulted in significant improvements in the production of cartilaginous matrix by articular chondrocytes, bone marrow-derived stem cells and nucleus pulposus cells (Paul et al 2003;Tsuchiya et al 2003;Tew et al 2005). Evidence indicated Quantification of DNA content, GAG production, and collagen content of cells: (A) The DNA content of chondrocytes cultured in vitro with 15 µg/ml, 30 µg/ml or 60 µg/ml taurine for 2, 4 or 6 days; (B) GAG (mg) normalized to DNA (mg); (C) The total collagen content (µg).…”

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confidence: 99%

Chondroprotective Effects of Taurine in Primary Cultures of Human Articular Chondrocytes

Liu

et al. 2015

Tohoku J. Exp. Med.

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Articular cartilage is characterized by the lack of blood vessels and has a poor self-healing potential. Limited cell numbers and dedifferentiation of chondrocytes when expanded in vitro are the major obstacles of autologous chondrocyte implantation. Autologous chondrocyte implantation is a cell-based treatment that can be used as a second-line measure to regenerate chondral or osteochondral defects in younger, active patients. There is an urgent need to find an effective chondrogenic protection agent alleviating or inhibiting chondrocyte dedifferentiation. In this study, we explored the effect of taurine (2-aminoethane sulfonic acid) on proliferation and phenotype maintenance of human articular chondrocytes by analyzing the cell proliferation, morphology, viability, and expression of cartilage specific mRNAs and proteins. Primary chondrocytes were isolated from human articular cartilage tissues. Results showed that taurine effectively promoted chondrocyte growth and enhanced accumulation of glycosaminoglycans and collagens in the conditioned media of chondrocytes. Moreover, taurine exposure caused significant increases in the relative expression levels of mRNAs for cartilage specific markers, including aggrecan, collagen type II and SOX9. Aggrecan is a cartilage-specific proteoglycan, and SOX9 is a chondrogenic transcription factor. In contrast, the mRNA expression of collagen type I, a marker for chondrocyte dedifferentiation, was significantly decreased in cells treated with taurine, indicating that taurine inhibits the chondrocyte dedifferentiation. This study reveals that taurine is effective in proliferation promotion and phenotype maintenance of chondrocytes. Thus, taurine may be a useful pro-chondrogenic agent for autologous chondrocyte implantation in the treatment of cartilage repair.

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“…Adenovirus vector was used to transfer the LMP-1 gene in anulous fibrosus cells and chondrocytes, where it similarly increased proteoglycan and collagen production (43). Transfection of degenerated human intervertebral disc cells with an adenovirus vector expressing SOX9 resulted in increased synthesis of collagen type II (44), restored the height of the degenerative rabbit intervertebral disc and promoted the expression of proteoglycan and collagen type II when administered with OP-1 as a dual gene therapy (45).…”

Section: Factors Enhancing Matrix Synthesismentioning

confidence: 99%

Biologic Treatment of Mild and Moderate Intervertebral Disc Degeneration

Vasiliadis

Pneumaticos

Evangelopoulos

et al. 2014

Mol Med

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Disc degeneration is the most common cause of back pain in adults and has enormous socioeconomic implications. Conservative management is ineffective in most cases, and results of surgical treatment have not yet reached desirable standards. Biologic treatment options are an alternative to the above conventional management and have become very attractive in recent years. The present review highlights the currently available biologic treatment options in mild and moderate disc degeneration, where a potential for regeneration still exists. Biologic treatment options include protein-based and cell-based therapies. Proteinbased therapies involve administration of biologic factors into the intervertebral disc to enhance matrix synthesis, delay degeneration or impede inflammation. These factors can be delivered by an intradiscal injection, alone or in combination with cells or tissue scaffolds and by gene therapy. Cell-based therapies comprise treatment strategies that aim to either replace necrotic or apoptotic cells, or minimize cell death. Cell-based therapies are more appropriate in moderate stages of degenerated disc disease, when cell population is diminished; therefore, the effect of administration of growth factors would be insufficient. Although clinical application of biologic treatments is far from being an everyday practice, the existing studies demonstrate promising results that will allow the future design of more sophisticated methods of biologic intervention to treat intervertebral disc degeneration.

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Potential Use of Sox9 Gene Therapy for Intervertebral Degenerative Disc Disease

Cited by 165 publications

References 44 publications

Cell-seeded polyurethane-fibrin structures – A possible system for intervertebral disc regeneration

Cell-seeded polyurethane-fibrin structures – A possible system for intervertebral disc regeneration

Chondroprotective Effects of Taurine in Primary Cultures of Human Articular Chondrocytes

Biologic Treatment of Mild and Moderate Intervertebral Disc Degeneration

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