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Originally published In Press as doi:10.1074/jbc.M200218200 on March 8, 2002

J. Biol. Chem., Vol. 277, Issue 21, 18860-18867, May 24, 2002
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Identification of STAT-1 as a Molecular Target of IGFBP-3 in the Process of Chondrogenesis*

Anna SpagnoliDagger §, Monica Torello§||, Srivinasa R. Nagalla**, William A. Horton||, Patrick Pattee**, Vivian Hwa**, Francesco ChiarelliDagger Dagger , Charles T. Roberts Jr.**, and Ron G. Rosenfeld**

From the Dagger  Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2579, the || Research Center, Shriners Hospital for Children, Portland, Oregon 97201, the ** Department of Pediatrics, Oregon Health & Science University, Portland, Oregon 97201, and the Dagger Dagger  Department of Pediatrics, University of Chieti, Chieti 66013, Italy

The chondrogenesis process requires the ordered proliferation and differentiation of chondrocytes. Insulin-like growth factor-binding protein (IGFBP)-3, well characterized as the carrier of insulin-like growth factor (IGF), 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: 1) that were regulated by IGFBP-3 in early but not in terminally differentiated chondrocytes; 2) that were regulated specifically by IGFBP-3, but not by IGF-I; and 3) whose regulation was abolished by coincubation of IGFBP-3 with IGF-I. Signal transducer and activator of transcription (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 phosphorylation and its nuclear localization. An antisense STAT-1 oligonucleotide 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.

* This work was supported in part by grant from the Medical Research Foundation of Oregon (to A. S.). This work was presented in part at the 83rd Annual Meeting of the Endocrine Society, Denver, June 2001 and the 6th Joint Meeting of the Lawson-Wilkins Pediatric Endocrine Society and European Society for Paediatric Endocrinology, Montreal, Canada, July 2001.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ These authors contributed equally to this work.

To whom correspondence should be addressed: Dept. of Pediatrics, Vanderbilt University Medical Center, T-0107 Medical Center North, Nashville, TN 37232-2579. E-mail: anna.spagnoli@mcmail.vanderbilt.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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