Treatment of experimental equine osteoarthritis by in vivo delivery of the equine interleukin-1 receptor antagonist gene

Frisbie, David D.; Ghivizzani, Steven C.; Robbins, Paul D.; Evans, Christopher H.; McIlwraith, C. Wayne

doi:10.1038/sj.gt.3301608

Cited by 337 publications

(377 citation statements)

References 31 publications

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“…Additional studies in established experimental models (7,8) will be required in order to evaluate the effects of SOX9 overexpression in OA cartilage in vivo. The present findings provide motivation to further develop this therapeutic gene-transfer approach to the treatment of OA in humans.…”

Section: Discussionmentioning

confidence: 99%

“…Application of therapeutic genes to OA cartilage may offer potent alternatives for reestab- Most of the current approaches to restoring the physiologic balance in injured articular cartilage are based on the delivery of factors that modulate the metabolic functions of chondrocytes, such as agents that counteract the processes of matrix degradation or ones that enhance the synthesis of matrix components. Protective effects of an IL-1 receptor antagonist (IL-1Ra) sequence against IL-1-induced cartilage breakdown have been documented in experimental models ex vivo (5,6) and in vivo (7,8). The transfer of the gene for a heat-shock protein (Hsp70) was also shown to afford protection against cellular injuries in chondrocytes (9).…”

mentioning

confidence: 99%

“…Protective effects of an IL-1 receptor antagonist (IL-1Ra) sequence against IL-1-induced cartilage breakdown have been documented in experimental models ex vivo (5,6) and in vivo (7,8). The transfer of the gene for a heat-shock protein (Hsp70) was also shown to afford protection against cellular injuries in chondrocytes (9).…”

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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

136

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: Discussionmentioning

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

136

220

View full text Add to dashboard Cite

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“…Mi et al 34 found that delivery of Ad.IGF-1 to the knees of normal rabbits and those with experimental arthritis was capable of stimulating an increase in proteoglycan synthesis in articular cartilage without adverse effects. Frisbie et al 35 found that delivery of an adenovirus encoding the equine homolog of IL-1Ra into the joints of horses with experimental OA resulted in significant clinical improvement in both pain and disease activity, and preservation of articular cartilage.…”

Section: Gene Transfer To Cells In the Synovial Liningmentioning

confidence: 99%

Gene-based approaches for the repair of articular cartilage

2004

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“…Anti-TNFα, PEGylated soluble TNFα (Fox & Stephens, 2010); (Frisbie et al, 2002); (Evans et al, 2004); (Meijer et al, 2003) (Zafarullah et al, 2003); (Martel-Pelletier, 1999); (Furman et al, 2006); (Fukui et al, 2001); (Evans et al, 2004); (Elsaid et al, 2009) Matrix protection…”

Section: Irap/ Il-1ramentioning

confidence: 99%