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Arthritis Res Ther. 2004; 6(5): R393–R403.
Published online Jun 28, 2004. doi:  10.1186/ar1201
PMCID: PMC546277
Pharmacological disruption of insulin-like growth factor 1 binding to IGF-binding proteins restores anabolic responses in human osteoarthritic chondrocytes
Frédéric De Ceuninck,corresponding author1 Audrey Caliez,1 Laurent Dassencourt,1 Philippe Anract,2 and Pierre Renard3
1Service de Rhumatologie, Institut de Recherches Servier, Suresnes, France
2Orthopédie B, Hôpital Cochin, Paris, France
3Service de Prospective et valorisation scientifique, Institut de Recherches Servier, Suresnes, France
corresponding authorCorresponding author.
Frédéric De Ceuninck: frederic.deceuninck/at/fr.netgrs.com
Received March 22, 2004; Revisions requested April 28, 2004; Revised May 5, 2004; Accepted May 19, 2004.
Abstract
Insulin-like growth factor 1 (IGF-1) has poor anabolic efficacy in cartilage in osteoarthritis (OA), partly because of its sequestration by abnormally high levels of extracellular IGF-binding proteins (IGFBPs). We studied the effect of NBI-31772, a small molecule that inhibits the binding of IGF-1 to IGFBPs, on the restoration of proteoglycan synthesis by human OA chondrocytes. IGFBPs secreted by human OA cartilage or cultured chondrocytes were analyzed by western ligand blot. The ability of NBI-31772 to displace IGF-1 from IGFBPs was measured by radiobinding assay. Anabolic responses in primary cultured chondrocytes were assessed by measuring the synthesis of proteoglycans in cetylpyridinium-chloride-precipitable fractions of cell-associated and secreted 35S-labeled macromolecules. The penetration of NBI-31772 into cartilage was measured by its ability to displace 125I-labeled IGF-1 from cartilage IGFBPs. We found that IGFBP-3 was the major IGFBP secreted by OA cartilage explants and cultured chondrocytes. NBI-31772 inhibited the binding of 125I-labeled IGF-1 to IGFBP-3 at nanomolar concentrations. It antagonized the inhibitory effect of IGFBP-3 on IGF-1-dependent proteoglycan synthesis by rabbit chondrocytes. The addition of NBI-31772 to human OA chondrocytes resulted in the restoration or potentiation of IGF-1-dependent proteoglycan synthesis, depending on the IGF-1 concentrations. However, NBI-31772 did not penetrate into cartilage explants. This study shows that a new pharmacological approach that uses a small molecule inhibiting IGF-1/IGFBP interaction could restore or potentiate proteoglycan synthesis in OA chondrocytes, thereby opening exciting possibilities for the treatment of OA and, potentially, of other joint-related diseases.
Keywords: articular cartilage, IGF-1, IGFBP, osteoarthritis, pharmacological treatment
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