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https://hdl.handle.net/2440/8788
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Type: | Journal article |
Title: | Regulation of insulin-like growth factor-binding protein-5 by insulin-like growth factor I and interleukin-1α in ovine articular chondrocytes |
Other Titles: | Regulation of insulin-like growth factor-binding protein-5 by insulin-like growth factor I and interleukin-1alpha in ovine articular chondrocytes |
Author: | Sunic, D. McNeil, J. Rayner, T. Andress, D. Belford, D. |
Citation: | Endocrinology, 1998; 139(5):2356-2362 |
Publisher: | Endocrine Press |
Issue Date: | 1998 |
ISSN: | 0013-7227 1945-7170 |
Statement of Responsibility: | Damir Sunic, Julian D. McNeil, Timothy E. Rayner, Dennis L. Andress, and David A. Belford |
Abstract: | Insulin-like growth factors (IGFs) contribute to the maintenance of the cartilage matrix by stimulating proteoglycan synthesis. In contrast, interleukin-1 (IL-1), an inflammatory cytokine, suppresses the synthesis of proteoglycans. In pathological conditions the chondrocytes’ responsiveness to IGF-I is decreased, and elevated levels of IGF-binding proteins (IGFBPs) have been implicated as a possible cause. The aim of this study was to investigate the effects of IGF-I and IL-1 on IGFBP production by ovine articular chondrocytes (OAC) and the roles of these IGFBPs in the regulation of proteoglycan synthesis. As revealed by Western ligand and immunoblotting, OACs secreted IGFBP-2 and a 24-kDa IGFBP in culture medium under basal conditions. Exposure of the cells to IGF-I for 48 h resulted in the appearance of IGFBP-5 in the medium. Des(1–3)IGF-I, an IGF-I analog with reduced affinity for IGFBPs, also increased the level of IGFBP-5, but to a lesser extent than IGF-I, whereas LR3IGF-I, which has virtually no affinity for IGFBPs, had no effect on IGFBP-5. Furthermore, IGFBP-5 underwent a time-dependent limited proteolysis when incubated with OAC-conditioned medium, degrading into 22- and 16-kDa fragments. The degradation of IGFBP-5 was significantly inhibited by IGF-I, but not by des(1–3)IGF-I or LR3IGF-I. Basic fibroblast growth factor, transforming growth factor-β, and platelet-derived growth factor had no effect on OAC IGFBPs. However, IL-1α increased the IGFBP-5 level in a dose-dependent manner, showing maximum activity at 200 U/ml. Furthermore, IL-1α, but not IGF-I, induced IGFBP-5 messenger RNA expression, as assessed by Northern blot analysis. Coincubation of IGF-I with IL-1α resulted in a substantially increased IGFBP-5 protein level, suggesting a synergism between the mechanisms of action of these two factors. Des(1–3)IGF-I and LR3IGF-I were 10 times more potent than IGF-I in stimulating proteoglycan synthesis, indicating inhibition of IGF-I activity by endogenous IGFBPs. IL-1α reduced the IGF-I bioactivity, but had no effect on the activities of the IGF-I analogs, thus implying that locally produced IGFBPs, particularly IGFBP-5, which was substantially increased when IGF-I and IL-1α were coincubated, mediated the reduction of the IGF-I activity. Our results demonstrate that IGF-I and IL-1α synergistically increase the level of IGFBP-5 in OAC by inhibiting the proteolysis and stimulating the expression of IGFBP-5, respectively. Furthermore, the attenuation of IGF-I-stimulated proteoglycan synthesis by IL-1α in OAC appears to be mediated by chondrocyte IGFBPs. We conclude that locally produced IGFBPs, in particular IGFBP-5, may play a critical role in the regulation of cartilage matrix degradation in inflammatory and degenerative arthritides. |
Keywords: | Cartilage, Articular Cells, Cultured Chondrocytes Animals Sheep Proteoglycans Fibroblast Growth Factor 2 Platelet-Derived Growth Factor Transforming Growth Factor beta Insulin-Like Growth Factor I Insulin-Like Growth Factor II Insulin-Like Growth Factor Binding Protein 5 RNA, Messenger Interleukin-1 Culture Media, Conditioned Immunoblotting Blotting, Western Gene Expression |
Rights: | Copyright status unknown |
DOI: | 10.1210/en.139.5.2356 |
Appears in Collections: | Aurora harvest 4 Medicine publications |
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