Transplantation of transduced chondrocytes protects articular cartilage from interleukin 1-induced extracellular matrix degradation.

Baragi, Vijaykumar M.; Renkiewicz, Richard R.; Jordan, Hollis; Bonadio, Jeffrey; Hartman, John W.; Roessler, Blake J.

doi:10.1172/jci118303

Cited by 143 publications

(89 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Direct application of rAAV-FLAG-hSOX9 to human normal and OA cartilage in situ mediated high levels of transgene expression that was distributed throughout the thickness of the explant cultures, probably due to the ability of these small vectors to penetrate the dense ECM of the cartilage (23,24). The manipulation of vectors such as rAAV might thus be desirable for introducing candidate genes directly into the targets as compared with other classes of vectors still used in ex vivo gene transfer protocols (5,12,45). While no effects on cell proliferation were seen, expression of the SOX9 gene cassette promoted a significant, dose-dependent increase in the proteoglycan and type II collagen content in OA cartilage to levels higher than or similar to those in the untreated normal cartilage and to depths relevant for clinical applications (24).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

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).…”

mentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…Chondrocytes cultured in monolayer are receptive to transduction using the more common viral vectors, including adenovirus, [47][48][49] oncoretrovirus (MoMLV), 50 VSV-G pseudotyped lentivirus 33 and AAV. 44,48,51 Although chondrocytes have been somewhat resistant to transfection with plasmid DNA, formulation with certain commercially available lipid-based reagents such as FuGENE6t 52,53 and Lipofectint has been found to enhance the efficiency of DNA uptake, as has pretreatment of the cells with hyaluronidase 54 and mild detergent.…”

Section: Chondrocytes As Targets For Gene Deliverymentioning

confidence: 99%

“…Genetically altered chondrocytes retain the ability to attach to and colonize cartilage explants in culture, 47 and following engraftment to the explant surface, are capable of expressing a transgene product at functional levels. Initial studies by Baragi et al 47 showed that in this context, chondrocytes adenovirally transduced to overexpress IL-1 receptor antagonist were resistant to IL-1-induced proteoglycan degradation.…”

Section: Chondrocytes As Targets For Gene Deliverymentioning

confidence: 99%

Gene-based approaches for the repair of articular cartilage

2004

View full text Add to dashboard Cite

“…22 Preclinical studies of gene transfer for cartilage repair have typically favored ex vivo approaches because they deliver chondrogenic cells and their expressed gene products to the defect site. In this regard, chondrocytes, periosteal cells and MSCs have been tested as vehicles for gene delivery in animal models, [23][24][25][26][27] and while there has been evidence of cartilage repair, clinical application would require harvesting and culturing of autologous cells for each patient. From our clinical experience with ex vivo gene delivery to joints, it has become evident that the facilities, labor, time and, therefore, expense of these procedures may make this approach impractical for mainstream application.…”

Section: Introductionmentioning

confidence: 99%

Gene delivery to cartilage defects using coagulated bone marrow aspirate

et al. 2004

View full text Add to dashboard Cite

The long-term goal of the present study is to develop a clinically applicable approach to enhance natural repair mechanisms within cartilage lesions by targeting bone marrow-derived cells for genetic modification. To determine if bone marrow-derived cells infiltrating osteochondral defects could be transduced in situ, we implanted collagen-glycosaminoglycan (CG) matrices preloaded with adenoviral vectors containing various marker genes into lesions surgically generated in rabbit femoral condyles. Analysis of the recovered implants showed transgenic expression up to 21 days; however, a considerable portion was found in the synovial lining, indicating leakage of the vector and/or transduced cells from the matrix. As an alternative medium for gene delivery, we investigated the feasibility of using coagulated bone marrow aspirates. Mixture of an adenoviral suspension with the fluid phase of freshly aspirated bone marrow resulted in uniform dispersion of the vector throughout, and levels of transgenic expression in direct proportion to the density of nucleated cells in the ensuing clot. Furthermore, cultures of mesenchymal progenitor cells, previously transduced ex vivo with recombinant adenovirus, were readily incorporated into the coagulate when mixed with fresh aspirate. These vector-seeded and cell-seeded bone marrow clots were found to maintain their structural integrity following extensive culture and maintained transgenic expression in this manner for several weeks. When used in place of the CG matrix as a gene delivery vehicle in vivo, genetically modified bone marrow clots were able to generate similarly high levels of transgenic expression in osteochondral defects with better containment of the vector within the defect. Our results suggest that coagulates formed from aspirated bone marrow may be useful as a means of gene delivery to cartilage and perhaps other musculoskeletal tissues. Cells within the fluid can be readily modified with an adenoviral vector, and the matrix formed from the clot is completely natural, native to the host and is the fundamental platform on which healing and repair of mesenchymal tissues is based.

show abstract

Transplantation of transduced chondrocytes protects articular cartilage from interleukin 1-induced extracellular matrix degradation.

Cited by 143 publications

References 25 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-based approaches for the repair of articular cartilage

Gene delivery to cartilage defects using coagulated bone marrow aspirate

Contact Info

Product

Resources

About