Effect of Somatomedin-C/Insulin-Like Growth Factor I and Growth Hormone on Cultured Growth Plate and Articular Chondrocytes

Trippel, Stephen B.; Corvol, Marie-Thérèse; Dumontier, Marie-France; Rappaport, R; Hung, Hsin-I; Mankin, Henry J.

doi:10.1203/00006450-198901000-00017

Cited by 139 publications

(69 citation statements)

References 29 publications

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“…The equilibrium dissociation constant as well as the number of binding sites on normal adult chondrocytes correlates well with previously published results using bovine, lapine, or rat chondrocytes (13,36,37). The presence of such a receptor on the chondrocyte membrane is also confirmed by the results of internalization experiments showing a rapid disappearance of radiolabeled IGF-1 from the cell membranes.…”

Section: Discussionsupporting

confidence: 89%

Human Osteoarthritic Chondrocytes Possess an Increased Number of Insulin‐Like Growth Factor 1 Binding Sites but are Unresponsive to its Stimulation

Doré

Pelletier

DiBattista

et al. 1994

Arthritis & Rheumatism

186

117

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Objective. To characterize the insulin-like growth factor 1 (IGF-1) receptor in human osteoarthritic (OA) and normal adult chondrocytes. The biologic response of chondrocytes to IGF-1 stimulation was examined, as was the presence and synthesis of IGF binding proteins (IGFBP) in these cells.Methods. Binding studies, Northern blot, immunohistochemical analysis, and affinity cross-linking experiments were performed for characterization of the IGF receptor, and the latter method was also used for IGFBP determination. The biologic response was estimated via the incorporation of radiolabeled proline into a newly synthesized protein.Results histochemical studies with a monoclonal antibody (MAb) against the type 1 IGF receptor (aIR3) showed increased staining in OA cartilage compared with normal tissue. Biologic responses of chondrocytes after IGF-1 stimulation revealed that OA chondrocytes were unresponsive, whereas a 2.5-fold increase in new protein synthesis was observed in normal cells. Competition studies in normal chondrocytes revealed that both IGF-1 and IGF-2 displaced radiolabeled IGF-1 in a comparable manner; however, insulin at high concentration weakly competes. Moreover, MAb aIR3 effectively blocked specific binding in normal chondrocytes (77 %), but not in OA chondrocytes (26%). Northern blot and covalent cross-linking analyses revealed the specific band characteristic of type 1 receptor. With the latter technique, other bands corresponding to the IGFBPs were also detected. Comparison between normal and OA chondrocytes showed increased intensity of the IGFBP bands, particularly those corresponding to the IGFBP-3 doublet.Conclusion. It is shown that type 1 IGF receptor is expressed in human articular cartilage and that the level of binding sites is significantly increased in OA chondrocytes. Interestingly, despite the higher level of binding sites in OA cells, no response to IGF-1 stimulation was found in these cells. Our data suggest that this increase in specific binding may involve not only the type 1 IGF receptor but also IGFBP on the cell surface. The latter, by binding the IGF-1, will diminish the bioavailability of IGF-1 and thus prevent its anabolic action.Osteoarthritis (OA) is the most common of the various arthritic disorders affecting humans. The dis-

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Section: Discussionsupporting

confidence: 89%

Human Osteoarthritic Chondrocytes Possess an Increased Number of Insulin‐Like Growth Factor 1 Binding Sites but are Unresponsive to its Stimulation

Doré

Pelletier

DiBattista

et al. 1994

Arthritis & Rheumatism

186

117

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“…We selected IGF-I for these studies based on previous work demonstrating that this factor augments chondrocyte mitotic activity, proteoglycan and type-II collagen synthesis, [7][8][9] new tissue formation by transplanted chondrocytes, 11 and the structural and functional properties of tissue-engineered cartilage. 12 Several in vivo studies further support the selection of IGF-I as a candidate for articular cartilage repair.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, it increases chondrocyte production of proteoglycan and type-II collagen, two principal constituents of cartilage. [7][8][9] The exogenous administration of human IGF-I has been reported to enhance the cell-based repair of articular cartilage defects. 3,6 Delivery of recombinant human IGF-I protein to articular cartilage has been achieved by intra-articular injection, 10 by supplementing a fibrin clot with IGF-I 3 and by combining composites of chondrocytes and polymerized fibrin with IGF-I.…”

Section: Introductionmentioning

confidence: 99%

Enhanced repair of articular cartilage defects in vivo by transplanted chondrocytes overexpressing insulin-like growth factor I (IGF-I)

et al. 2005

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Traumatic articular cartilage lesions have a limited capacity to heal. We tested the hypothesis that overexpression of a human insulin-like growth factor I (IGF-I) cDNA by transplanted articular chondrocytes enhances the repair of fullthickness (osteochondral) cartilage defects in vivo. Lapine articular chondrocytes were transfected with expression plasmid vectors containing the cDNA for the Escherichia coli lacZ gene or the human IGF-I gene and were encapsulated in alginate. The expression patterns of the transgenes in these implants were monitored in vitro for 36 days. Transfected allogeneic chondrocytes in alginate were transplanted into osteochondral defects in the trochlear groove of rabbits. At three and 14 weeks, the quality of articular cartilage repair was evaluated qualitatively and quantitatively. In vitro, IGF-I secretion by implants constructed from IGF-I-transfected chondrocytes and alginate was 123.2722.3 ng/10 7 cells/24 h at day 4 post transfection and remained elevated at day 36, the longest time point evaluated. In vivo, transplantation of IGF-I implants improved articular cartilage repair and accelerated the formation of the subchondral bone at both time points compared to lacZ implants. The data indicate that allogeneic chondrocytes, transfected by a nonviral method and cultured in alginate, are able to secrete biologically relevant amounts of IGF-I over a prolonged period of time in vitro. The data further demonstrate that implantation of these composites into deep articular cartilage defects is sufficient to augment cartilage defect repair in vivo. These results suggest that therapeutic growth factor gene delivery using encapsulated and transplanted genetically modified chondrocytes may be applicable to sites of focal articular cartilage damage.

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“…Concentrations of IGF-1 as low as 50 ng/mL are sufficient to exert significant effects on the proliferative and metabolic functions of cultured chondrocytes [6,13,31,34,44]. IGF-1 may therefore be more effective on differentiated chondrocytes than inducing chondrogenic differentiation of MSCs.…”

Section: Discussionmentioning

confidence: 99%

“…As an attempt to circumvent the problems associated with the above-mentioned approaches for cartilage repair, novel approaches that include gene and stem cell therapies are being evaluated [6,7]. Adult-derived stem cells that can be harvested from bone, fat, or muscle offer alternative sources for chondrocytes [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Adenoviral-mediated transfer of TGF-β1 but not IGF-1 induces chondrogenic differentiation of human mesenchymal stem cells in pellet cultures

Kawamura¹,

Chu²,

Sobajima³

et al. 2005

Experimental Hematology

102

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Objective. The objective of the present study was to investigate the potential of application of growth factor genes to induce chondrogenic differentiation of human-derived mesenchymal stem cells (MSCs). The growth factor genes evaluated in the present study were transforming growth factor 1 (TGF-β1) and insulin-like growth factor 1 (IGF-1).Methods. Human MSCs were transduced with the adenoviral vectors carrying either TGF-β1 or IGF-1 (AdTGF-β1 and AdIGF-1 respectively) or a combination of both growth factor genes at different multiplicities of infection (MOI) and were then made into pellets. Pellets were also made from nontransduced cells and maintained in culture medium supplemented with 10 ng/mL of TGF-β1. At specified time points, histological analysis, cartilage matrix gene expression, and immunofluorescence were performed to determine the extent of chondrogenic differentiation.Results. MSCs transduced with the AdTGF-β1 demonstrated robust chondrogenic differentiation, while those made from AdIGF-1 did not. AdTGF-β1 pellets demonstrated aggrecan gene expression as early as day 3 of pellet culture, while type II collagen gene expression was detected by day 10 of culture. The AdIGF-1, alone or in combination with TGF-β1 pellets, did not show any type II collagen gene expression at any time point. By immunofluoresecence, type X collagen was distributed throughout the matrix in TGF-β1 protein pellets while the growth factor gene pellets displayed scant staining. Conclusion.The results suggest that sustained administration of TGF-β1 may be more effective in suppressing terminal differentiation than intermittent dosing and thus effective for cartilage repair.

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Effect of Somatomedin-C/Insulin-Like Growth Factor I and Growth Hormone on Cultured Growth Plate and Articular Chondrocytes

Cited by 139 publications

References 29 publications

Human Osteoarthritic Chondrocytes Possess an Increased Number of Insulin‐Like Growth Factor 1 Binding Sites but are Unresponsive to its Stimulation

Human Osteoarthritic Chondrocytes Possess an Increased Number of Insulin‐Like Growth Factor 1 Binding Sites but are Unresponsive to its Stimulation

Enhanced repair of articular cartilage defects in vivo by transplanted chondrocytes overexpressing insulin-like growth factor I (IGF-I)

Adenoviral-mediated transfer of TGF-β1 but not IGF-1 induces chondrogenic differentiation of human mesenchymal stem cells in pellet cultures

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