Pharmacological disruption of insulin-like growth factor 1 binding to IGF-binding proteins restores anabolic responses in human osteoarthritic chondrocytes

Arthritis Research & Therapy
Frédéric De CeuninckPierre Renard

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 ...Continue Reading

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Citations

Mar 8, 2007·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Jessica E MalbergSharon Rosenzweig-Lipson
Feb 23, 2018·International Journal of Molecular Sciences·Magdalena Krajewska-WłodarczykJoanna Wojtkiewicz
Dec 1, 2007·Journal of Orthopaedic Research : Official Publication of the Orthopaedic Research Society·Teresa I Morales
Jan 18, 2008·The Journal of Pathology·Mi GuillénMj Alcaraz
Mar 4, 2020·Tissue Engineering. Part a·Matthew Anderson-BaronAdetola B Adesida
Jun 15, 2014·Annals of the Rheumatic Diseases·Daniel S EvansNancy E Lane
Sep 16, 2020·Drug Development Research·Amresh KumarManabendra Dutta Choudhury
Oct 1, 2011·International Journal of Immunopathology and Pharmacology·O GalassoG Gasparini
Mar 9, 2010·Biochemical Pharmacology·Maria José AlcarazMaria Isabel Guillén

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Methods Mentioned

BETA
FCS
lavage
electrophoresis

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