SOX9 expression does not correlate with type II collagen expression in adult articular chondrocytes

Aigner, Thomas; Gebhard, Pia M.; Schmid, Erik; Bau, Brigitte; Harley, Vincent R.; Pöschl, Ernst

doi:10.1016/s0945-053x(03)00049-0

Cited by 143 publications

(127 citation statements)

References 47 publications

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“…In contrast, the FLAG tag was detected only in rAAV-FLAG-hSOX9-transduced treated cartilage (results not shown). SOX9 expression, however, was observed in normal and OA explant cultures where either vector was applied ( Figure 3), which is consistent with the previously reported results of SOX9 expression in cartilage (22). However, marked differences were noted depending on the vector applied and the type of cartilage evaluated.…”

Section: Expression Of a Sox9 Gene Cassette In Human Articular Chondrsupporting

confidence: 91%

“…The rAAV-FLAG-hSOX9 vector carries a human SOX9 cDNA tagged by a FLAG sequence to discriminate between the endogenous SOX9 (18,22) and the transgene. Chondrocytes were next encapsulated in alginate spheres and maintained in culture for 26 days.…”

Section: Expression Of a Sox9 Gene Cassette In Human Articular Chondrmentioning

confidence: 99%

“…SOX9 is expressed during embryonic development in a pattern that closely parallels that of cartilage matrix synthesis (17) and exerts its properties by activating the gene for type II collagen and other cartilage-specific genes (17)(18)(19)(20). Notably, the levels of SOX9 expression decline in OA cartilage (21,22). Modulation of the chondrocyte phenotype in OA cartilage by genetically modifying the levels of intracellular SOX9 expression might be advantageous in shifting the disrupted balance toward the synthesis of ECM components and contribute to the reproduction of an original articular cartilage surface.…”

mentioning

confidence: 99%

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Restoration of the extracellular matrix in human osteoarthritic articular cartilage by overexpression of the transcription factor SOX9

Cucchiarini¹,

Thurn²,

Weimer³

et al. 2007

Arthritis & Rheumatism

137

220

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Objective. Human osteoarthritis (OA) is characterized by a pathologic shift in articular cartilage homeostasis toward the progressive loss of extracellular matrix (ECM). The purpose of this study was to investigate the ability of rAAV-mediated SOX9 overexpression to restore major ECM components in human OA articular cartilage.Methods. We monitored the synthesis and content of proteoglycans and type II collagen in 3-dimensional cultures of human normal and OA articular chondrocytes and in explant cultures of human normal and OA articular cartilage following direct application of a recombinant adeno-associated virus (rAAV) SOX9 vector in vitro and in situ. We also analyzed the effects of this treatment on cell proliferation in these systems.Results. Following SOX9 gene transfer, expression levels of proteoglycans and type II collagen increased over time in normal and OA articular chondrocytes in vitro. In situ, overexpression of SOX9 in normal and OA articular cartilage stimulated proteoglycan and type II collagen synthesis in a dose-dependent manner. These effects were not associated with changes in chondrocyte proliferation. Notably, expression of the 2 principal matrix components could be restored in OA articular cartilage to levels similar to those in normal cartilage.Conclusion. These data support the concept of using direct, rAAV-mediated transfer of chondrogenic genes to articular cartilage for the treatment of OA in humans.Osteoarthritis (OA) is a progressive disease that affects diarthrodial joints and is mainly characterized by a gradual deterioration of the articular cartilage. A disturbed balance in cartilage metabolism is thought to play an important role in the pathogenesis of OA and to be a key factor in determining its progression. Over the course of OA, the cartilage loses major components of its extracellular matrix (ECM), such as proteoglycans and type II collagen (1). Proinflammatory cytokines, such as interleukin 1 (IL-1) and tumor necrosis factor ␣, produced locally by the inflamed synovium likely contribute to the pathophysiology of OA (2). Articular chondrocytes are the focus of OA because of pathologic changes in their gene expression pattern (3), the loss of their capacity to synthesize cartilage-specific matrix molecules, and their increased production of matrixdegrading enzymes (4).Despite various therapeutic options, including systemic nonsteroidal antiinflammatory drugs, local corticosteroids, physical therapy, regular exercise, use of orthopedic appliances, or with the advent of disease-and structure-modifying drugs, the management of OA remains an unresolved problem, especially for patients who are too young to undergo endoprosthetic total joint replacement. The difficulty in treating OA is largely due to its slow and irreversible progression and to the limited intrinsic ability of the cartilage to reequilibrate its natural components. Application of therapeutic genes to OA cartilage may offer potent alternatives for reestab- Most of the current approaches to restoring the physiolog...

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Section: Expression Of a Sox9 Gene Cassette In Human Articular Chondrsupporting

confidence: 91%

Section: Expression Of a Sox9 Gene Cassette In Human Articular Chondrmentioning

confidence: 99%

mentioning

confidence: 99%

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Restoration of the extracellular matrix in human osteoarthritic articular cartilage by overexpression of the transcription factor SOX9

Cucchiarini¹,

Thurn²,

Weimer³

et al. 2007

Arthritis & Rheumatism

137

220

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show abstract

“…The transcription factor Sox9, considered a crucial factor in chondrogenesis and cartilage formation in vivo, may not correlate with chondrocyte dedifferentiation during in vitro cultivation. 23 This stable expression of Sox9 in serially passaged chondrocytes suggests that other transcription factors may govern the dedifferentiation process, and that it may be reversible. [24][25][26][27] Chondrocytes maintain a homeostatic anabolic and catabolic balance of extracellular matrix (ECM) via regulation of secreted matrix proteinases and protease inhibitors to maintain the composition and structural integrity of ECM in articular cartilage.…”

mentioning

confidence: 98%

Gene expression profiles of human chondrocytes during passaged monolayer cultivation

Lin

Fitzgerald

et al. 2008

Journal Orthopaedic Research

180

149

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Chondrocyte phenotype has been shown to dedifferentiate during passaged monolayer cultivation. Hence, we have investigated the expression profile of 27 chondrocyte-associated genes from both osteoarthritic cartilage tissue and healthy passaged human articular chondrocytes by quantitative real-time PCR. Our results indicate that the gene expression levels of matrix proteins and proteases in chondrocytes from monolayer culture decrease compared with those from cartilage tissue, while monolayer cultured chondrocytes from normal and osteoarthritic cartilage exhibit similar gene expression patterns. However, chondrocytic gene expression profiles were differentially altered at various stages of passage. The expression of the matrix proteins aggrecan, type II collagen, and fibromodulin inversely correlated with increasing passage number, while fibronectin and link protein exhibited a marked increase with passage. The expression of matrix proteinases MMP-3/9/13 and ADAMTS-4/5 decreased with passage, whereas proteinase inhibitors TIMP-2/3 were elevated. The cytokine IL-1 also showed increased expression with monolayer chondrocyte culture, while IGF-1 expression levels were diminished. No significant changes in TGF-b, or the chondrogenic transcription factors Sox-9, c-fos, or c-jun were observed. Our data indicates that cultured chondrocytes undergo dedifferentiation during monolayer culture, although the gene expression level of transcription factors necessary for chondrogenesis remains unchanged. This data may prove important for the future development of more specific and efficacious cultivation techniques for human articular chondrocyte-based therapies. ß

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“…However, another study showed no significant difference in subcellular expression of Sox9 protein between osteoarthritic and normal control human cartilage. Sox9 overexpression did not correlate with collagen-2 expression in adult articular cartilage, suggesting that Sox9 is not a key regulator of collagen-2 expression in human adult articular chondrocytes (Aigner et al, 2003). Furthermore, in vitro studies showed that overexpression of Sox9 was unable to restore the chondrocyte phenotype of dedifferentiated osteoarthritic articular chondrocytes (Kypriotou et al, 2003).…”

Section: Sox9mentioning

confidence: 97%

Transcriptional Regulation of Articular Chondrocyte Function and Its Implication in Osteoarthritis

Wang¹,

Kramer²,

Schroeppel³

2012

Principles of Osteoarthritis- Its Definition, Character, Derivation and Modality-Related Recognition

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SOX9 expression does not correlate with type II collagen expression in adult articular chondrocytes

Cited by 143 publications

References 47 publications

Restoration of the extracellular matrix in human osteoarthritic articular cartilage by overexpression of the transcription factor SOX9

Restoration of the extracellular matrix in human osteoarthritic articular cartilage by overexpression of the transcription factor SOX9

Gene expression profiles of human chondrocytes during passaged monolayer cultivation

Transcriptional Regulation of Articular Chondrocyte Function and Its Implication in Osteoarthritis

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