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J. Biol. Chem., Vol. 283, Issue 49, 34037-34044, December 5, 2008

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Stimulatory Effects of Insulin-like Growth Factor-I on Growth Plate Chondrogenesis Are Mediated by Nuclear Factor-B p65^*

From the Section of Endocrinology and Diabetes, St. Christopher's Hospital for Children, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, Pennsylvania 19134

Insulin-like growth factor-I (IGF-I) is an important regulator of endochondral ossification. However, little is known about the signaling pathways activated by IGF-I in growth plate chondrocytes. We have previously shown that NF-B-p65 facilitates growth plate chondrogenesis. In this study, we first cultured rat metatarsal bones with IGF-I and/or pyrrolidine dithiocarbamate (PDTC), a known NF-B inhibitor. The IGF-I-mediated stimulation of metatarsal growth and growth plate chondrogenesis was neutralized by PDTC. In rat growth plate chondrocytes, IGF-I induced NF-B-p65 nuclear translocation. The inhibition of NF-B-p65 expression and activity (by p65 short interfering RNA and PDTC, respectively) in chondrocytes reversed the IGF-I-mediated induction of cell proliferation and differentiation and the IGF-I-mediated prevention of cell apoptosis. Moreover, the inhibition of the phosphatidylinositol 3-kinase and Akt abolished the effects of IGF-I on NF-B activation. In conclusion, our findings indicate that IGF-I stimulates growth plate chondrogenesis by activating NF-B-p65 in chondrocytes.

Received for publication, May 15, 2008 , and in revised form, October 14, 2008.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: St. Christopher's Hospital for Children, Erie Ave. at Front St., Philadelphia, PA 19134. Tel.: 215-427-8101; Fax: 215-427-8105; E-mail: francesco.deluca{at}drexelmed.edu.

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