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Some molecular mechanisms of glucocorticoid action
1Harvard Medical School, Massachusetts General Hospital, Boston 02114.
Abstract:
Glucocorticoids, in excess, profoundly affect the skeleton by increasing bone resorption, decreasing bone formation and altering intestinal absorption and renal excretion of mineral ions. The mechanisms underlying these actions are complex but many involve changes in expression of genes encoding critical proteins. Interaction of the glucocorticoid with its nuclear receptor results in the induction of either positive events (transactivation) by direct interaction with cis-acting sequences, or negative (transrepression) events by repression of gene transcription and/or alteration of mRNA half-lives. An example is the inhibition by glucocorticoids of collagenase synthesis. Induction of the collagenase (procollagenase) gene by inflammatory mediators, such as interleukin-1, can be inhibited by glucocorticoid transrepression. The glucocorticoid-receptor complex binds to a protein complex AP-1; consisting of the proteins c-JUN and c-FOS) and prevents this complex from inducing activation of the procollagenase gene. These observations may be applicable to the interpretation of other glucocorticoid actions and explain some of their adverse effects on the skeleton.
Insights
Excess glucocorticoids harm bones by increasing resorption and decreasing formation. Glucocorticoid receptor interactions can inhibit gene expression, like collagenase synthesis, potentially explaining skeletal side effects.
Area of Science:
- Endocrinology
- Molecular Biology
- Bone Biology
Background:
- Glucocorticoids significantly impact skeletal health, affecting bone resorption, formation, and mineral ion balance.
- These effects are mediated by complex mechanisms involving alterations in gene expression.
- Glucocorticoid actions occur via nuclear receptor interactions, leading to transactivation or transrepression.
Purpose of the Study:
- To elucidate the molecular mechanisms by which excess glucocorticoids adversely affect the skeleton.
- To explain how glucocorticoid receptor interactions influence gene expression related to bone metabolism.
- To provide a framework for understanding glucocorticoid-induced skeletal pathologies.
Main Methods:
- Analysis of glucocorticoid interactions with nuclear receptors.
- Investigation of gene expression changes induced by glucocorticoids.
- Examination of the molecular mechanisms of transactivation and transrepression.
Main Results:
- Glucocorticoid-receptor complex interactions modulate gene expression, impacting critical proteins.
- Glucocorticoids inhibit collagenase synthesis through transrepression.
- The glucocorticoid-receptor complex interferes with the AP-1 complex (c-JUN and c-FOS), preventing procollagenase gene activation.
Conclusions:
- Glucocorticoid-induced transrepression of specific genes, such as collagenase, contributes to adverse skeletal effects.
- Understanding these molecular interactions is crucial for interpreting glucocorticoid actions on bone.
- These findings offer insights into the pathogenesis of glucocorticoid-induced osteoporosis and related conditions.