PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of arthrestherBioMed Centralbiomed central web sitesearchsubmit a manuscriptregisterthis articleArthritis Research & Therapy
 
Arthritis Res Ther. 2004; 6(5): R393–R403.
Published online 2004 June 28. 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

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

Articles from Arthritis Research & Therapy are provided here courtesy of BioMed Central