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Adenovirus-Mediated Expression of Dominant Negative Fibroblast Growth Factor (FGF) Receptor 1 in Thyroid Cells Blocks FGF Effects and Reduces Goitrogenesis in Mice

Division of Medical Sciences (E.L.D., J.D.R., H.C., A.L., J.A.F., M.C.E.) and Cancer Research UK United Kingdom Institute for Cancer Research (P.F.S., V.M.), University of Birmingham, and Department of Otolaryngology, University Hospital Birmingham National Health Service Trust (J.C.W.), Birmingham, United Kingdom B15 2TT; and University of Occupational and Environmental Health School of Medicine (H.U.), Kitakyushu 807-8555, Japan

Address all correspondence and requests for reprints to: Dr. M. C. Eggo, The Medical School, University of Birmingham, Birmingham, United Kingdom B15 2TT. E-mail: m.c.eggo{at}bham.ac.uk.

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 ¹²⁵I 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.

This work was supported by a project grant from the Wellcome Trust, a fellowship award from the Medical Research Council (to J.D.R.), and a fellowship award from the GetAHead Campaign and the Royal College of Surgeons (to H.C.C.).

Abbreviations: 8BrcAMP, 8-Bromo-cAMP; CMV, cytomegalovirus; DN, dominant negative; EGF, epidermal growth factor; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; GFP, green fluorescent protein; HBSS, Hanks’ Balanced Salt Solution; MOI, multiplicity of infection; pfu, plaque-forming units; RAd, replication-defective adenovirus; Vv, volume density.

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