Browsing by Author "Mercer, Scott"

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    Endogenous versus Exogenous Growth Factor Regulation of Articular Chondrocytes
    (Wiley, 2014) Shi, Shuiliang; Chan, Albert G.; Mercer, Scott; Eckert, George J.; Trippel, Stephen B.; Orthopaedic Surgery, School of Medicine
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    Growth factor regulation of growth factor production by multiple gene transfer to chondrocytes
    (Taylor & Francis, 2013) Shi, Shuiliang; Mercer, Scott; Eckert, George J.; Trippel, Stephen B.; Orthopaedic Surgery, School of Medicine
    Of the many classes of molecules regulated by growth factors, growth factors themselves are not well investigated. We tested the hypothesis that combinations of endogenous growth factors interactively regulate the production of other growth factors. Growth factors have therapeutic potential for articular cartilage repair, and gene transfer is a promising approach to growth factor delivery. We tested the hypothesis using adult bovine articular chondrocytes treated with combinations of cDNAs encoding insulin-like growth factor I, bone morphogenetic protein-2 and protein-7, transforming growth factor β1, and fibroblast growth factor 2. We found that these growth factor transgenes regulated each other's growth factor production. This regulation ranged from stimulation to inhibition. Regulation by multiple transgenes was not predictable from the regulatory actions of the individual transgenes. Such interactions may be important for the selection of growth factor genes for cell-based therapies, including articular cartilage repair.
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    Growth Factor Transgenes Interactively Regulate Articular Chondrocytes
    (Wiley, 2013) Shi, Shuiliang; Mercer, Scott; Eckert, George J.; Trippel, Stephen B.; Orthopaedic Surgery, School of Medicine
    Adult articular chondrocytes lack an effective repair response to correct damage from injury or osteoarthritis. Polypeptide growth factors that stimulate articular chondrocyte proliferation and cartilage matrix synthesis may augment this response. Gene transfer is a promising approach to delivering such factors. Multiple growth factor genes regulate these cell functions, but multiple growth factor gene transfer remains unexplored. We tested the hypothesis that multiple growth factor gene transfer selectively modulates articular chondrocyte proliferation and matrix synthesis. We tested the hypothesis by delivering combinations of the transgenes encoding insulin-like growth factor I (IGF-I), fibroblast growth factor-2 (FGF-2), transforming growth factor beta1 (TGF-β1), bone morphogenetic protein-2 (BMP-2), and bone morphogenetic protien-7 (BMP-7) to articular chondrocytes and measured changes in the production of DNA, glycosaminoglycan, and collagen. The transgenes differentially regulated all these chondrocyte activities. In concert, the transgenes interacted to generate widely divergent responses from the cells. These interactions ranged from inhibitory to synergistic. The transgene pair encoding IGF-I and FGF-2 maximized cell proliferation. The three-transgene group encoding IGF-I, BMP-2, and BMP-7 maximized matrix production and also optimized the balance between cell proliferation and matrix production. These data demonstrate an approach to articular chondrocyte regulation that may be tailored to stimulate specific cell functions, and suggest that certain growth factor gene combinations have potential value for cell-based articular cartilage repair.
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    Regulation of articular chondrocyte catabolic genes by growth factor interaction
    (Wiley, 2019-02-27) Shi, Shuiliang; Mercer, Scott; Eckert, George J.; Trippel, Stephen B.; Orthopaedic Surgery, School of Medicine
    Osteoarthritis is characterized by a loss of articular cartilage homeostasis in which degradation exceeds formation. Several growth factors have been shown to promote cartilage formation by augmenting articular chondrocyte anabolic activity. This study tests the hypothesis that such growth factors also play an anti-catabolic role. We transferred individual or combinations of the genes encoding insulin- like growth factor I, bone morphogenetic protein-2, bone morphogenetic protein-7, transforming growth factor-β1 and fibroblast growth factor-2, into adult bovine articular chondrocytes and measured the expression of catabolic marker genes encoding A disintegrin and metalloproteinase with thrombospondin motifs-4 and −5, matrix metalloproteinases-3 and −13, and interleukin-6. When delivered individually, or in combination, these growth factor transgenes differentially regulated the direction, magnitude and time course of expression of the catabolic marker genes. In concert, the growth factor transgenes regulated the marker genes in an interactive fashion that ranged from synergistic inhibition to synergistic stimulation. Synergistic stimulation prevailed over synergistic inhibition, reaching maxima of 15.2-fold and 2.7-fold, respectively. Neither the magnitude nor the time course of the effect of the transgene combinations could be predicted on the basis of the individual transgene effects. With few exceptions, the data contradict our hypothesis. The results demonstrate that growth factors that are traditionally viewed as chondrogenic tend also to promote catabolic gene expression. The competing actions of these potential therapeutic agents add an additional level of complexity to the selection of regulatory factors for restoring articular cartilage homeostasis or promoting repair.