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G A Rodan

Publications and source records attributed to G A Rodan.

200 records · Page 12Linked to original sources
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The aminobisphosphonate alendronate inhibits bone loss induced by thyroid hormone in the rat. Comparison between effects on tibiae and vertebrae.

The aims of this study were to develop a rat model of hyperthyroidism and to determine the efficacy of alendronate in the prevention of thyroid hormone-induced bone loss. Ten week-old Sprague-Dawley rats injected with thyroxine 250 micrograms/kg/day (+T4) or vehicle (-T4) were treated with alendronate (+ALN) or vehicle (-ALN) orally 0.5 mg/kg/day. After 3 weeks of treatment histomorphometric parameters of cancellous bone remodeling were assessed in the proximal tibia and in the first lumbar vertebra. In the secondary spongiosa of the tibia T4 treatment caused significant bone loss, associated with increased bone turnover; trabecular bone volume, trabecular thickness and trabecular number were significantly decreased. Osteoid and osteoclast surfaces increased in +T4/-ALN as compared to control. Alendronate prevented the increase in bone turnover and increased bone volume above control values without interfering with the recruitment of osteoclasts. These changes were not apparent in the vertebra. It is concluded that excess thyroid hormone in the rat induces high turnover bone loss in the tibia which can be prevented by alendronate through an inhibition of osteoclastic activity. The lack of effects of thyroid hormone on the vertebra may be ascribed to a lower rate of basal bone turnover at that site.

Alendronate↗
PubMedDate not supplied

Structural requirements and cell-type specificity for ligand activation of peroxisome proliferator-activated receptors.

The mammalian peroxisome proliferator-activated receptor (PPAR) family consists of three different subtypes, PPARalpha, hNUC1/PPARdelta and PPARgamma. Selective agonists have been identified for PPARalpha and PPARgamma but not for hNUC1, and consequently little is known about the genes that are controlled by this receptor. Using ligand-dependent transcription assays in COS-7 cells, we screened a variety of PPAR activating agents to identify a selective activator of hNUC1. We found that the potent peroxisome proliferator, Wy-14643, and the PPARgamma-selective thiazolidinedione, BRL 49653, were poor activators of hNUC1 (EC50s of > 100 microM). Short chain fatty acids (FAs) appeared more selective for PPARalpha than for hNUC1, whereas the very long chain FA, erucic acid (C22:1) was more selective for hNUC1. Using erucic acid as a probe, we conducted a topological similarity search of the Merck Chemical Collection and identified a fatty acid-like compound, L-631,033 4-(2-acetyl-6-hydroxyundecyl) cinnamic acid, that was a selective activator of hNUC1 (EC50 of 2 microM), but was much less selective for PPARalpha or PPARgamma (EC50s of > 100 microM). Structure-function analysis of PPAR activation by L-631,033 structural analogues showed that receptor selectivity depends on the position of the carboxyl group relative to the phenyl ring on the molecule. Transfection experiments in several cell types: an osteoblastic cell line (MB 1.8), a mouse liver cell line (ML-457), rat aortic smooth muscle cells (RSMCs) and COS-7 cells revealed differences in the activation profile of specific ligands. The most notable differences were observed in RSMCs, where transactivation by L-631,033 and Wy-14643, but not by BRL 49653, was markedly reduced, and in MB 1.8 cells, where oleic acid failed to activate PPARs. These findings identify certain structural features in PPAR-activating agents that modulate PPAR activation, and suggest that as with other nuclear receptors, activation is cell-type specific.

Animals↗