Acceleration of cartilage repair by genetically modified chondrocytes over expressing bone morphogenetic protein‐7

Abstract

Abstract. Buc,kgrouiit/ Cartilage has a limited capacity to heal. Although chondrocyte transplantation is a useful therapeutic strategy, the repair process can be lengthy. Previously we have shown that over expression of bone morphogenetic protein-7 (BMP-7) in chondrocytes by adenovirus-mediated gene transfer leads to increased matrix synthesis and cartilage-like tissue formation in vitro. In this context we hypothesized that implantation of genetically modified chondrocytes expressing BMP-7 would accelerate the formation of hyaline-like repair tissue in an equine model of cartilage defect repair.Met/io(l.s: Chondrocytes treated with adenovirus vector encoding BMP-7 (AdBMP-7) or as control. an adenovirus vector encoding an irrelevant gene (Esdierichiu coli cytosine deaminase, AdCD) were implanted into extensive ( I5 mm diameter) articular cartilage defects in the patellofemoral joints of 10 horses. Biopsies were performed to evaluate early healing at 4 weeks. At the terminal time point of 8 months, repairs were assessed for morphology, MRI appearance, compressive strength, biochemical composition and persistence of implanted cells.Residts: Four weeks after surgery AdBMP-7-treated repairs showed an increased level of BMP-7 expression and accelerated healing, with markedly more hyaline-like morphology than control. Quantitative real-time polymerase chain reaction (PCR) analysis of the repair tissue 8 months after surgery showed that few implanted cells persisted. By this time, the controls had healed similarly to the AdBMP-7-treated defects, and no difference was detected in the morphologic, biochemical or biomechanical properties of the repair tissues from the two treatment groups.Conc/ir.siorzs: Implantation of genetically modified chondrocytes expressing BMP-7 accelerates the appearance of hyaline-like repair tissue in experimental cartilage defects.Clinical rele[wxx>: Rehabilitation after cell-based cartilage repair can be prolonged, leading to decreased patient productivity and quality of life. This study shows the feasibility of using genetically modified chondrocytes to accelerate cartilage healing.

Differences in matrix accumulation and hypertrophy in superficial and deep zone chondrocytes are controlled by bone morphogenetic protein

“…We and others have reported that exogenous BMPs also increase matrix synthesis by chondrocytes (Flechtenmacher et al, 1996;Hidaka et al, 2003;Hidaka et al, 2001;Huch et al, 1997;Sailor et al, 1996). In the current study, we have identified SZC as the sub-population that is particularly responsive, even to low doses of BMPs.…”

“…Previously, we have reported increased matrix gene expression and matrix synthesis in chondrocytes overexpressing BMP7 (Hidaka et al, 2001). Furthermore, we showed that BMP7 overexpressing chondrocytes can be implanted into experimental cartilage defects to accelerate repair in vivo (Hidaka et al, 2003).…”

Gene-based approaches for the repair of articular cartilage

“…65,66 A similar trend was seen with BMP-7 with a variation of 0-28% of transplanted chondrocytes surviving in the defect at 8 months. 67 These results are encouraging in that they demonstrate that genetic modification of chondrocytes can be used to augment cartilage repair processes in a large animal model. They also suggest that the stability of the therapeutic benefit is linked to the persistence of transgene expression.…”

“…Two recent reports have described ex vivo gene transfer to cartilage lesions in the horse using allogenic chondrocytes, adenovirally transduced to express equine IGF-1 65,66 or BMP-7. 67 Following genetic modification, the cells were incorporated in a matrix of autogenous fibrin implanted into surgically generated 15 mm full-thickness cartilage lesions. In the defects of animals receiving chondrocytes modified with Ad.IGF-1, accelerated cartilage repair was evident.…”

“…Overall, the levels of collagen type II and proteoglycan, and the mechanical characteristics of the healing tissue were similar in BMP-7-transduced defects and defects containing cells expressing an irrelevant transgene. 67 To provide insight into the fate of the chondrocytes postdelivery, a portion of each of the previous two studies entailed the use of modified chondrocytes derived from male donors implanted in female recipients. Quantitative PCR was then used to detect the presence of the SRY-gene marker in recovered tissue samples.…”