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M200218200v1
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Papers In Press, published online ahead of print March 8, 2002
J. Biol. Chem, 10.1074/jbc.M200218200
Submitted on January 8, 2002
Revised on March 6, 2002
Accepted on March 7, 2002

Identification of STAT-1 as a molecular target of insulin-like growth factor binding protein-3 (IGFBP-3) in the process of chondrogenesis

Anna Spagnoli, Monica Torello, Srivinasa R. Nagalla, William A. Horton, Patrick Pattee, Vivian Hwa, Francesco Chiarelli, Charles T. Roberts Jr, and Ron G. Rosenfeld

Division of Pediatric Endocrinology, Vanderbilt University Medical Center, Nashville, TN 37232-2579

Corresponding Author: anna.spagnoli{at}mcmail.vanderbilt.edu

Summary Chondrogenesis process requires the ordered proliferation and differentiation of chondrocytes. Insulin-like growth factor binding protein-3 (IGFBP-3), well characterized as IGFs carrier, has been reported to have intrinsic bioactivity that is independent of IGF binding. The mechanisms involved in this IGF-independent action are still unclear. Using the RCJ3.1C5.18 chondrogenic cells, which in culture progresses from undifferentiated to terminally differentiated chondrocytes, we have shown previously that IGFBP-3 has an IGF-independent, antiproliferative effect in undifferentiated and early differentiated but not in terminally differentiated chondrocytes. In the present study, cDNA microarray analysis was used to screen for genes that were: 1) regulated by IGFBP-3 in early but not in terminally differentiated chondrocytes; 2) regulated specifically by IGFBP-3, but not by IGF-I; and 3) whose regulation was abolished by co-incubation of IGFBP-3 with IGF-I. STAT-1 was the gene that, fulfilling the screening criteria, exhibited the greatest up-regulation by IGFBP-3 (>40-fold). STAT-1 gene up-regulation was confirmed by Northern analysis of cells treated with IGFBP-3 or transfected with an IGFBP-3 expression vector. Remarkably, similar results were obtained when cells were transfected with an IGFBP-3 mutant unable to bind IGFs, definitively demonstrating the IGF-independent action of IGFBP-3. Consistent with the up-regulation of STAT-1 mRNA, IGFBP-3 also increased STAT-1 protein expression. Furthermore, both IGFBP-3 and the IGFBP-3 mutant induced STAT-1 phosporylation and its nuclear localization. An antisense STAT-1-oligo abolished the IGF-independent cell apoptosis induced by IGFBP-3. We have demonstrated that STAT-1 is a major intracellular signaling and transcriptional target of the IGF-independent apoptotic effect of IGFBP-3 in chondrogenesis.


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