title: Pharmacological disruption of insulin-like growth factor 1 binding to IGF-binding proteins restores anabolic responses in human osteoarthritic chondrocytes.
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.
authors.affiliation: Service de Rhumatologie, Institut de Recherches Servier, Suresnes, France. frederic.deceuninck@fr.netgrs.com
authors.forename: Frédéric
authors.initials: F
authors.lastname: De Ceuninck
authors.forename: Audrey
authors.initials: A
authors.lastname: Caliez
authors.forename: Laurent
authors.initials: L
authors.lastname: Dassencourt
authors.forename: Philippe
authors.initials: P
authors.lastname: Anract
authors.forename: Pierre
authors.initials: P
authors.lastname: Renard
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002358:Cartilage, Articular / Q000378:metabolism; D002396:Catechols / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology*; D007457:Iodine Radioisotopes / Q000378:metabolism; D007546:Isoquinolines / Q000378:metabolism / Q000494:pharmacology; D010003:Osteoarthritis / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011509:Proteoglycans / Q000096:biosynthesis; D011817:Rabbits; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology
chemical_list: D002396:Catechols; D018969:Insulin-Like Growth Factor Binding Proteins; D007457:Iodine Radioisotopes; D007546:Isoquinolines; C436731:NBI 31772; D011509:Proteoglycans; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I