No abstract

Thyroid hormone (T3) and the T3 receptor (TR) alpha gene are essential for bone development whereas adult hyperthyroidism increases the risk of osteoporotic fracture. We isolated fibroblast growth factor receptor-1 (FGFR1) as a T3-target gene in osteoblasts by subtraction hybridization. FGFR1 mRNA was induced 2- to 3-fold in osteoblasts treated with T3 for 6-48 h, and FGFR1 protein was stimulated 2- to 4-fold. Induction of FGFR1 was independent of mRNA half-life and abolished by actinomycin D and cycloheximide, indicating the involvement of an intermediary protein. Fibroblast growth factor 2 (FGF2) stimulated MAPK in osteoblasts, and pretreatment with T3 for 6 h induced a more rapid response to FGF that was increased in magnitude by 2- to 3-fold. Similarly, T3 enhanced FGF2-activated autophosphorylation of FGFR1, but did not modify FGF2-induced phosphorylation of the docking protein FRS2. These effects were abolished by the FGFR-selective inhibitors PD166866 and PD161570. In situ hybridization analyses of TRalpha-knockout mice, which have impaired ossification and skeletal mineralization, revealed reduced FGFR1 mRNA expression in osteoblasts and osteocytes, whereas T3 failed to stimulate FGFR1 mRNA or enhance FGF2-activated MAPK signaling in TRalpha-null osteoblasts. These findings implicate FGFR1 signaling in T3-dependent bone development and the pathogenesis of skeletal disorders resulting from thyroid disease.

No abstract

Catecholamines increase not only oxygen delivery to tissues but also oxygen consumption (VO2). The effect of an infusion of dopamine hydrochloride has been studied at two doses, each in six dogs. Dopamine 10 micrograms kg-1 min-1 caused an increase in haemoglobin concentration and altered cardiac output, oxygen availability and total body oxygen consumption such that oxygen availability ratio increased and (CaO2-CVO2) decreased although these changes were not statistically significant. Dopamine 30 micrograms kg-1 min-1 increased (P less than 0.05) heart rate, haemoglobin concentration and CaO2 and significantly reduced stroke volume and VD/VT. Although oxygen availability increased, increases in oxygen consumption were greater and this resulted in a statistically insignificant reduction in oxygen availability ratio and an increase in (CaO2-CVO2). Terminating the dopamine infusion resulted in significant (P less than 0.05) decreases in cardiac output, PVO2, CaO2), oxygen availability and oxygen consumption and an increase in (CaO2-CVO2). It was concluded that maximum oxygen delivery occurs at a lower dose than that required to produce the maximum increase in oxygen consumption.