Exogenous insulin-like growth factor-I stimulates an autoinductive IGF-I autocrine/paracrine response in chondrocytes

The modulation of insulin-like growth factor-I (IGF-I) gene expression by c hondrocytes following exogenous IGF-I supplementation of culture was assess ed to examine the hypothesis that constitutive IGF-I mRNA activity is suppr essed by exogenous administration of IGF-I to cartilage in situ. Chodrocyte s in monolayer culture were treated with 0, 10 or 100 ng/ml TGF-I for 48 h and resultant IGF-I and matrix gene expression patterns were assessed by qu antitative polymerase chain reaction (qPCR) and northern blotting, respecti vely. Effective translation of proteoglycan (PG) as a response to IGF-I was determined by dimethylmethylene blue (DMMB) dye-binding assay. To determin e the temporal nature of the IGF-I autocrine/paracrine response to exogenou s IGF-I, chondrocyte cultures were treated with 100 ng/ml IGF-I and the IGF -I mRNA response was assessed at 0, 4, 12, 24, 48 and 72 h. Significant inc reases in chondrocyte density and hi Pe synthesis occurred during treatment of chondrocyte cultures with 10 and l()0 ng/ml IGF-I, Persistent exposure of chondrocytes to 100 ng/ml IGF-T resulted in maximal IGF-I mRNA response at 21 h, with declining message accumulation at 38 and 72 h. These data sug gest that IGF-I induces an autoinductive IGF-I autocrine/paracrine transcri ptional response. The clinical ramifications of these findings include supp ort for the use of exogenous IGF-I for cartilage repair where it could conc eivably amplify and extend the effect of exogenous IGF-I beyond the transit ory persistence of supplemental IGF-I ligand in repair constructs. (C) 2001 Orthopaedic Research Society. Published by Elsevier Science Ltd. All right s reserved.