Hormonal regulation of glycosaminoglycan accumulation in fibroblasts from patients with resistance to thyroid hormone.
We have previously shown that physiological concentrations of T3 added to thyroid hormone-deficient media decreased the incorporation of [3H]acetate and [3H]glucosamine into glycosaminoglycans (GAG) in confluent cultures of skin fibroblasts obtained from normal individuals. This inhibitory effect of T3 on [3H]GAG accumulation was due to a decrease in GAG synthesis, was independent of the substrate pool size or number of transfers in culture, and could be reversed by removal of hormone from the medium. As shown in the current communication, it was also independent of the site of biopsy and age and sex of the donor. Fibroblast cultures were grown to confluence in medium containing 10% fetal calf serum and then exposed for 3 days to medium deprived of thyroid hormone (10% bovine serum from a thyroidectomized animal) without or with the addition of T3, T4, or dexamethasone (DEX). After exposure to labeled substrate [(3H]acetate or [3H]glucosamine) for the last 24 h, their incorporation into GAG was determined. The mean +/- SD maximal inhibition of [3H]GAG accumulation in fibroblasts from 14 normal subjects was 38.3 +/- 14.4% compared to 22.4 +/- 13.0% in fibroblasts from 8 patients with generalized resistance to thyroid hormone (GRTH). Although the difference was significant at the group level (P less than 0.05), there was a considerable overlap between the results obtained from normal subjects and those from patients with GRTH. Furthermore, fibroblasts from 2 normal subjects failed to respond to T3 in several trials. The specificity of the effect of T3 was examined in fibroblast cultures from eight normal subjects and six patients with GRTH by comparing their responsiveness to T3 and to DEX. All fibroblasts obtained from normal subjects that responded to T3 also responded to DEX. Fibroblasts from the two normal individuals that did not respond to T3 also failed to respond to T4 and to DEX. In contrast, fibroblasts from four of the six patients with GRTH had an attenuated response to T3, but not to DEX. Fibroblasts from a patient with Marfan's syndrome responded normally to T3 despite increased incorporation of the substrate into GAG. The maximal inhibitory effect of T4 on [3H]GAG accumulation was identical to that of T3. However, a 100-fold higher concentration of T4 was required.(ABSTRACT TRUNCATED AT 400 WORDS)
D000293:Adolescent; D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D002648:Child; D003907:Dexamethasone / Q000494:pharmacology; D004351:Drug Resistance; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006025:Glycosaminoglycans / Q000096:biosynthesis*; D006801:Humans; D007223:Infant; D008297:Male; D013963:Thyroid Hormones / Q000494:pharmacology*; D013974:Thyroxine / Q000494:pharmacology; D014284:Triiodothyronine / Q000494:pharmacology
D006025:Glycosaminoglycans; D013963:Thyroid Hormones; D014284:Triiodothyronine; D003907:Dexamethasone; D013974:Thyroxine