TY - JOUR
T1 - Adenovirus-mediated expression of dominant negative fibroblast growth factor (FGF) receptor 1 in thyroid cells blocks FGF effects and reduces goitrogenesis in mice
AU - Davies, EL
AU - Ramsden, JD
AU - Cocks, H
AU - Searle, Peter
AU - Watkinson, John
AU - Ueno, H
AU - Logan, Ann
AU - Franklyn, Jayne
AU - Mautner, Vivien
AU - Eggo, Margaret
PY - 2003/9/1
Y1 - 2003/9/1
N2 - Levels of fibroblast growth factor 2 (FGF-2) and its receptor, FGFR1, are elevated in goiter, but whether this is a direct effect of TSH is unknown. We have determined the regulation of FGF-2 and FGFR1 synthesis by TSH in a rat thyroid cell line (FRTL5) and have used a replication-defective adenovirus (RAd) expressing dominant negative FGFR1 (RAdDN-FGFR1) to examine the role of FGFR signaling in vitro and in goiter induced in mice. TSH induced FGF-2 and increased the expression of FGFR1 in FRTL5 cells. Infection of TSH-stimulated FRTL5 cells with RAdDN-FGFR1 inhibited growth and prevented FGF-2-mediated inhibition of (125)I uptake. Similar effects were found in primary cultures of human thyroid follicular cells. For in vivo experiments, male BALB/c mice were injected systemically with RAdDN-FGFR1 or RAd encoding green fluorescent protein, and goiter was simultaneously induced. Mouse thyroid follicles were shown to be transduced with RAd encoding green fluorescent protein. Circulating TSH was elevated comparably in the two groups. In the RAdDN-FGFR1-injected animals, goiter induced over 14 d was significantly smaller, and the vascular volume increase seen in goiter was also diminished. We conclude that the FGF axis is important in thyroid growth and that RAdDN-FGFR1 effectively blocks FGF actions, offering a means to control goitrogenesis.
AB - Levels of fibroblast growth factor 2 (FGF-2) and its receptor, FGFR1, are elevated in goiter, but whether this is a direct effect of TSH is unknown. We have determined the regulation of FGF-2 and FGFR1 synthesis by TSH in a rat thyroid cell line (FRTL5) and have used a replication-defective adenovirus (RAd) expressing dominant negative FGFR1 (RAdDN-FGFR1) to examine the role of FGFR signaling in vitro and in goiter induced in mice. TSH induced FGF-2 and increased the expression of FGFR1 in FRTL5 cells. Infection of TSH-stimulated FRTL5 cells with RAdDN-FGFR1 inhibited growth and prevented FGF-2-mediated inhibition of (125)I uptake. Similar effects were found in primary cultures of human thyroid follicular cells. For in vivo experiments, male BALB/c mice were injected systemically with RAdDN-FGFR1 or RAd encoding green fluorescent protein, and goiter was simultaneously induced. Mouse thyroid follicles were shown to be transduced with RAd encoding green fluorescent protein. Circulating TSH was elevated comparably in the two groups. In the RAdDN-FGFR1-injected animals, goiter induced over 14 d was significantly smaller, and the vascular volume increase seen in goiter was also diminished. We conclude that the FGF axis is important in thyroid growth and that RAdDN-FGFR1 effectively blocks FGF actions, offering a means to control goitrogenesis.
UR - http://www.scopus.com/inward/record.url?scp=0141564523&partnerID=8YFLogxK
U2 - 10.1210/jc.2003-030333
DO - 10.1210/jc.2003-030333
M3 - Article
C2 - 12970326
SN - 1945-7197
VL - 88
SP - 4472
EP - 4480
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 9
ER -