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Hormonal Regulation of Glycosaminoglycan Accumulation in Fibroblasts from Patients with Resistance to Thyroid Hormone^*

YOSHIHARU MURATA, SAMUEL REFETOFF, ALLEN L. HORWITZ and TERRY J. SMITH

Thyroid Study Unit, Department of Medicine, and the Department of Pediatrics, University of Chicago Chicago, Illinois 60637

Address all corresponce and requests for reprints to: Samuel Refetoff, M.D., University of Chicago, Thyroid Study Unit-Box 138, 950 East 59th Street, Chicago, Illinois 60637.

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 < 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. The amount of intracellular T₃ generated from T₄, calculated on the basis of cellular uptake of T₄ and its conversion to T₃, almost fully accounts for the effect of T₃ on the inhibition of GAG synthesis.

The failure to demonstrate specific resistance to T₃ in fibroblasts from the two patients in whom the diagnosis of GRTH was established on clinical grounds remains unexplained. Several possibilities exist: these patients may have a lesser of T₃ resistance, their skin fibroblasts may not universally share the resistance to T₃ action with other body tissues, or the defect may not always include steps involved in the action of thyroid hormone on GAG synthesis.

^* This work was supported in part by USPHS Grants AM-15070, AM-07011, and RR-305 and the Kennedy Foundation.

Present address: Division of Metabolic and Endocrine Disease, Medical College of Georgia, Augusta, Georgia 30912.

Received May 9, 1983.

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