Hyperthyroidism is associated with increased bone resorption but the mechanisms by which thyroid hormone (T3) affects bone cell metabolism remain unclear. Recently it has been suggested that T3 stimulates osteoclastic resorption indirectly through the release of soluble mediators from osteoblasts. The aim of the present study was to investigate whether the T3-induced increase in bone resorption could be due to the regulation of cytokine production by human osteoblasts (hOb).The effects of T3 (1, 10, 100 nM) and IL-1 (100 U/ml) as the positive control were examined on cytokine protein release and mRNA levels in cultured hOb cell lines (MG63, SaOs-2), primary hOb and human bone marrow stromal (hBMS) cells. T3 increased IL-6 and IL-8 mRNA levels as well as IL-6 and IL-8 protein release into the culture media from MG63 and hBMS cells in a time-and dose-dependent manner. The maximal effect on protein release in hBMS cells occurred at 24 h with a dose of T3 10 nM (IL-6 5·5 1·1-fold above controls; IL-8 3·7 0·5-fold above controls, P<0·05). At the same time, mRNA levels in hBMS cells were increased 6·2 0·8-fold for IL-6 (P<0·05) and 5·7 0·8-fold for IL-8 (P<0·05). Similar results were obtained in MG63 cells but no response was seen in SaOs-2 or hOb cells despite measurable basal production. Nor was there detectable regulation of IL-1 , IL-3, IL-11, IL-4 or granulocyte macrophage-colony stimulating factor by T3 in any cell type.In conclusion, T3 increases IL-6 and IL-8 production by MG63 and hBMS cells, suggesting that IL-6 and IL-8 may be T3-regulated genes in osteoblasts.
Ten insulin-dependent C-peptide-negative diabetic subjects, whose control had been optimized on twice-daily injection therapy, were treated for periods of 10 wk in a crossover study, with either a thrice-daily subcutaneous insulin injection regimen (Actrapid + Ultratard) or by continuous subcutaneous insulin infusion (CSII). On CSII insulin dose stabilized at 51 +/- 5 U/day, compared with 80 +/- 9 U/day (P = 0.004) on the thrice-daily injection regimen, having been 60 +/- 6 U/day on twice-daily therapy. After 10 wk glycosylated hemoglobin was 11.7 +/- 0.6% on injection therapy and 10.0 +/- 0.7% (P = 0.026) on CSII. Mean blood glucose concentration and urinary glucose excretion were lower at most points during the study on CSII than on injection therapy. Patients on pumps gained weight compared with the thrice-daily injection regimen (P = 0.023 at 10 wk) and the previous twice-daily regimen, despite the reduction in insulin dose. Considering individual patients, four markedly improved on CSII compared with the previous twice-daily regimen and five compared with Actrapid + Ultratard. No patient showed impaired control on CSII compared with either injection regimen. The benefits of portable insulin infusion pumps over injection therapy are thus clearly demonstrable under outpatient conditions even with equal and intensive medical attention.
The aim of the present study was to examine whether triiodo-L-thyronine (T 3 ) or L-thyroxine (T 4 ) rapidly activated the mitogen-activated protein kinase (MAPK) intracellular signalling cascade in osteoblast-like cells and investigate whether this activation was initiated at the integrin a V b 3 cell surface receptor. Using PCR and western blotting, the expression of integrin a V b 3 mRNA and protein was demonstrated in the human osteoblast-like cell lines MG-63 and SaOS-2. The treatment of MG-63 cells with T 3 (10 nM) or T 4 (100 nM) for 10 min stimulated extracellular signal-regulated kinase activity (ERK, a component of the MAPK pathway) as determined by fluorescent immunocytochemistry and an immunocomplex activity assay (T 3 by 10 . 7-fold, P!0 . 01 and T 4 by 10 . 4-fold, P!0 . 01 compared with control). T 3 (10 nM) and T 4 (100 nM) also significantly stimulated thymidine incorporation into MG-63 cells by 2 . 3G0 . 7-fold (P!0 . 01) and 2 . 1G0 . 1-fold (P!0 . 05) respectively. To establish whether transient ERK activation via the integrin a V b 3 cell surface receptor mediated these effects, MG-63 cells were pretreated for 30 min with the specific MAPK kinase inhibitor, U0126 (1 mM), or an antiintegrin a V b 3 -blocking antibody. Both pretreatments significantly inhibited T 3 -and T 4 -stimulated ERK activation and abolished T 3 -stimulated thymidine incorporation (P!0 . 01).T 4 -stimulated incorporation was significantly inhibited from 2 . 1-to 1 . 3-fold above control (P!0 . 05). Thus, our results suggest that T 3 and T 4 rapidly stimulate ERK activation in MG-63 cells via integrin a V b 3 and that one functional effect of this ERK activation is increased DNA synthesis.
SUMMARY The effect of hypothyroxinaemia on postnatal progression of the motor nerve conduction velocity was studied in 33 very low birthweight infants.Serum concentrations of thyroid stimulating hormone, triiodothyronine, and thyroxine were determined at birth and at ages 3, 7, and 21 days. Nerve conduction velocity was measured in the first week of life, on day 21, and at 40 weeks' postmenstrual age.
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