This Article Full Text Full Text (PDF) All Versions of this Article: 146/7/3096    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kiepe, D. Articles by Tönshoff, B. Search for Related Content PubMed PubMed Citation Articles by Kiepe, D. Articles by Tönshoff, B.

Insulin-Like Growth Factor (IGF)-I Stimulates Cell Proliferation and Induces IGF Binding Protein (IGFBP)-3 and IGFBP-5 Gene Expression in Cultured Growth Plate Chondrocytes via Distinct Signaling Pathways

University Children’s Hospital (D.K., S.C., B.T.), 69120 Heidelberg; and Institute of Molecular Animal Breeding and Biotechnology/Gene Center (A.H., E.W.), 81377 Munich, Germany

Address all correspondence and requests for reprints to: Burkhard Tönshoff, M.D., Ph.D., University Children’s Hospital, Im Neuenheimer Feld 153, 69120 Heidelberg, Germany. E-mail: burkhard_toenshoff{at}med.uni-heidelberg.de.

The bioactivity of IGF-I in the cellular microenvironment is modulated by both inhibitory and stimulatory IGF binding proteins (IGFBPs), whose production is partially under control of IGF-I. However, little is known on the IGF-mediated regulation of these IGFBPs in the growth plate. We therefore studied the effect of IGF-I on IGFBP synthesis and the involved intracellular signaling pathways in two cell culture models of rat growth plate chondrocytes. In growth plate chondrocytes in primary culture, incubation with IGF-I increased the concentrations of IGFBP-3 and IGFBP-5 in conditioned cell culture medium in a dose- and time-dependent manner. Coincubation of IGF-I with specific inhibitors of the p42/44 MAPK pathway (PD098059 or U0126) completely abolished the stimulatory effect of IGF-I on IGFBP-3 mRNA expression but did not affect increased IGFBP-5 mRNA levels. In contrast, inhibition of the phosphatidylinositol-3 kinase signaling pathway by LY294002 abrogated both IGF-I-stimulated IGFBP-3 and -5 mRNA expression. Comparable results regarding IGFBP-5 were obtained in the mesenchymal chondrogenic cell line RCJ3.1C5.18, which does not express IGFBP-3. The IGF-I-induced IGFBP-5 gene expression required de novo mRNA transcription and de novo protein synthesis. These data suggest that IGF-I modulates its activity in cultured rat growth plate chondrocytes by the synthesis of both inhibitory (IGFBP-3) and stimulatory (IGFBP-5) binding proteins. The finding that IGF-I uses different and only partially overlapping intracellular signaling pathways for the regulation of two IGFBPs with opposing biological functions might be important for the modulation of IGF bioactivity in the cellular microenvironment.

This article has been cited by other articles:

				D. Kiepe, A. Van Der Pas, S. Ciarmatori, L. Standker, B. Schutt, A. Hoeflich, U. Hugel, J. Oh, and B. Tonshoff Defined Carboxy-Terminal Fragments of Insulin-Like Growth Factor (IGF) Binding Protein-2 Exert Similar Mitogenic Activity on Cultured Rat Growth Plate Chondrocytes as IGF-I Endocrinology, October 1, 2008; 149(10): 4901 - 4911. [Abstract] [Full Text] [PDF]

				S. Perrini, A. Natalicchio, L. Laviola, A. Cignarelli, M. Melchiorre, F. De Stefano, C. Caccioppoli, A. Leonardini, S. Martemucci, G. Belsanti, et al. Abnormalities of Insulin-Like Growth Factor-I Signaling and Impaired Cell Proliferation in Osteoblasts from Subjects with Osteoporosis Endocrinology, March 1, 2008; 149(3): 1302 - 1313. [Abstract] [Full Text] [PDF]

				T. Yokota, H. Shimokawa, S. Shibata, K. Itoh, Y. Baba, K. Ohya, K. Ohyama, and S. Suzuki Insulin-like Growth Factor I Regulates Apoptosis in Condylar Cartilage J. Dent. Res., February 1, 2008; 87(2): 159 - 163. [Abstract] [Full Text] [PDF]

				A. Marchini, B. Hacker, T. Marttila, V. Hesse, J. Emons, B. Weiss, M. Karperien, and G. Rappold BNP is a transcriptional target of the short stature homeobox gene SHOX Hum. Mol. Genet., December 15, 2007; 16(24): 3081 - 3087. [Abstract] [Full Text] [PDF]

				K. E. Govoni, S. K. Lee, Y.-S. Chung, R. R. Behringer, J. E. Wergedal, D. J. Baylink, and S. Mohan Disruption of insulin-like growth factor-I expression in type II{alpha}I collagen-expressing cells reduces bone length and width in mice Physiol Genomics, August 20, 2007; 30(3): 354 - 362. [Abstract] [Full Text] [PDF]

				J. M Fleming, J. A Brandimarto, and W. S Cohick The mitogen-activated protein kinase pathway tonically inhibits both basal and IGF-I-stimulated IGF-binding protein-5 production in mammary epithelial cells J. Endocrinol., August 1, 2007; 194(2): 349 - 359. [Abstract] [Full Text] [PDF]

				M. R. Hutchison, M. H. Bassett, and P. C. White Insulin-Like Growth Factor-I and Fibroblast Growth Factor, But Not Growth Hormone, Affect Growth Plate Chondrocyte Proliferation Endocrinology, July 1, 2007; 148(7): 3122 - 3130. [Abstract] [Full Text] [PDF]

				C. J. Xian Roles of Epidermal Growth Factor Family in the Regulation of Postnatal Somatic Growth Endocr. Rev., May 1, 2007; 28(3): 284 - 296. [Abstract] [Full Text] [PDF]

				S. Ciarmatori, D. Kiepe, A. Haarmann, U. Huegel, and B. Tonshoff Signaling mechanisms leading to regulation of proliferation and differentiation of the mesenchymal chondrogenic cell line RCJ3.1C5.18 in response to IGF-I J. Mol. Endocrinol., April 1, 2007; 38(4): 493 - 508. [Abstract] [Full Text] [PDF]

				A. A. Samani, S. Yakar, D. LeRoith, and P. Brodt The Role of the IGF System in Cancer Growth and Metastasis: Overview and Recent Insights Endocr. Rev., February 1, 2007; 28(1): 20 - 47. [Abstract] [Full Text] [PDF]

				M. A Meester-Smoor, A. C Molijn, Y. Zhao, N. A Groen, C. A H Groffen, M. Boogaard, D. van Dalsum-Verbiest, G. C Grosveld, and E. C Zwarthoff The MN1 oncoprotein activates transcription of the IGFBP5 promoter through a CACCC-rich consensus sequence J. Mol. Endocrinol., January 1, 2007; 38(1): 113 - 125. [Abstract] [Full Text] [PDF]

				C. H. Lang, B. J. Krawiec, D. Huber, J. M. McCoy, and R. A. Frost Sepsis and inflammatory insults downregulate IGFBP-5, but not IGFBP-4, in skeletal muscle via a TNF-dependent mechanism Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2006; 290(4): R963 - R972. [Abstract] [Full Text] [PDF]

				D. Kiepe, S. Ciarmatori, A. Haarmann, and B. Tonshoff Differential expression of IGF system components in proliferating vs. differentiating growth plate chondrocytes: the functional role of IGFBP-5 Am J Physiol Endocrinol Metab, February 1, 2006; 290(2): E363 - E371. [Abstract] [Full Text] [PDF]

				M. Granado, T. Priego, A. I. Martin, M{a} A. Villanua, and A. Lopez-Calderon Ghrelin receptor agonist GHRP-2 prevents arthritis-induced increase in E3 ubiquitin-ligating enzymes MuRF1 and MAFbx gene expression in skeletal muscle Am J Physiol Endocrinol Metab, December 1, 2005; 289(6): E1007 - E1014. [Abstract] [Full Text] [PDF]