Activation of fibroblast growth factor receptor 3 (FGFR3) leads to attenuation of cartilage growth. The members of the STAT family of transcription factors are believed to participate in FGFR3 signaling in cartilage, however the molecular mechanism of this action is poorly understood. Here, we demonstrate that a chronic FGF stimulus leads to accumulation of STAT1, 3, 5 and 6, evident in both in vitro chondrocyte model and murine limb explant cultures. Despite the accumulation, both endogenous and cytokine-induced activation of STAT1 and STAT3 is impaired by FGF, as demonstrated by imaging of active STAT nuclear translocation and analyses of STAT activatory phosphorylation and transcriptional activation. Further, we demonstrate that FGF induces expression of CIS, SOCS1 and SOCS3 inhibitors of gp130, a common receptor for the IL6-family of cytokines. Since cytokine-gp130 signaling represents an important positive regulator of cartilage, its inhibition may contribute to the growth-inhibitory effect of FGFR3 in cartilage.

Institute of Experimental Biology Masaryk University 61137 Brno Czech Republic

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Passos-Bueno MR, Wilcox WR, Jabs EW, Sertie AL, Alonso LG, Kitoh H. Hum Mutat. 1999;14:115–125. PubMed

Legeai-Mallet L, Benoist-Lasselin C, Delezoide A, Munnich A, Bonaventure J. J Biol Chem. 1998;273:13007–13014. PubMed

Legeai-Mallet L, Benoist-Lasselin C, Munnich A, Bonaventure J. Bone. 2004;34:26–36. PubMed

Chen L, Adar R, Yang X, Monsonego E, Li C, Hauschka PV, Yayon A, Deng C. J Clin Invest. 1999;104:1517–1525. PubMed PMC

Li C, Chen L, Iwata T, Kitagawa M, Fu X, Deng C. Hum Mol Genet. 1999;8:35–41. PubMed

Sahni M, Ambrosetti D, Mansukhani A, Gertner R, Levy D, Basilico C. Genes Dev. 1999;13:1361–1366. PubMed PMC

Sahni M, Raz R, Coffin JD, Levy D, Basilico C. Development. 2001;128:2119–2129. PubMed

Krejci P, Bryja V, Pachernik J, Hampl A, Pogue R, Mekikian P, Wilcox WR. Exp Cell Res. 2004;297:152–164. PubMed

Chin YE, Kitagawa M, Su WS, You ZH, Iwamoto Y, Fu XY. Science. 1996;272:719–722. PubMed

Nowroozi N, Raffioni S, Wang T, Apostol BL, Bradshaw RA, Michels Thompson L. Hum Mol Genet. 2005;14:1529–1538. PubMed

Krejci P, Salazar L, Goodridge HS, Kashiwada TA, Schibler M, Jelinkova P, Michels Thompson L, Wilcox WR. J Cell Sci. 2008;121:272–281. PubMed

Minina E, Wenzel HM, Kreschel C, Karp S, Gaffield W, McMahon AP, Vortkamp A. Development. 2001;128:4523–4534. PubMed

Köstner M, Hauser H. Eur J Biochem. 1999;260:137–144. PubMed

Watanabe K, Saito K, Kinjo M, Matsuda T, Tamura M, Kon S, Miyazaki T, Uede T. Biochem Biophys Res Commun. 2004;324:1264–1273. PubMed

Herrmann A, Sommer U, Pranada AL, Giese B, Haan S, Becker W, Heinrich PC, Müller-Neven G. J Cell Sci. 2003;116:339–349. PubMed

Aikawa T, Segre GV, Lee K. J Biol Chem. 2001;276:29347–29352. PubMed

Rozenblatt-Rosen O, Mosonego-Ornan E, Sadot E, Madar-Shapiro L, Sheinin Y, Ginsberg D, Yayon A. J Cell Sci. 2002;115:553–562. PubMed

Dailey L, Laplantine E, Priore R, Basilico C. J Cell Biol. 2003;161:1053–1066. PubMed PMC

Raucci A, Laplantine E, Mansukhani A, Basilico C. J Biol Chem. 2004;279:1747–1756. PubMed

Krejci P, Masri B, Fontaine V, Mekikian PB, Weis M, Prats H, Wilcox WR. J Cell Sci. 2005;118:5089–5100. PubMed

Priore R, Dailey L, Basilico C. J Cell Physiol. 2006;207:800–808. PubMed

Ben-Zvi T, Yayon A, Gertler A, Monsonego-Ornan E. J Cell Sci. 2005;119:380–387. PubMed

Aaronson DS, Horvath CM. Science. 2002;269:1653–1655. PubMed

Decker T, Kovarik P. Oncogene. 2000;19:2628–2637. PubMed

Yoshimura A, Naka T, Kubo M. Nat Rev Immunol. 2007;7:454–464. PubMed

Yamamoto K, Yamaguchi M, Miyasaka N, Miura O. Biochem Biophys Res Commun. 2003;310:1188–1193. PubMed

Qing Y, Costa-Pereira AP, Watling D, Stark GR. J Biol Chem. 2005;280:1849–1853. PubMed

Dagoneau N, Scheffer D, Huber C, Al-Gazali LI, Di Rocco M, Godard A, Martinovic J, Raas-Rothschild A, Sigaudy S, Unger S, et al. Am J Hum Genet. 2004;74:298–305. PubMed PMC

Sims NA, Jenkins BJ, Quinn JM, Nakamura A, Glatt M, Gillespie MT, Ernst M, Martin TJ. J Clin Invest. 2004;113:379–389. PubMed PMC

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