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04:33
Primary Culture of Rat Adrenocortical Cells and Assays of Steroidogenic Functions
Published on: March 12, 2019
3-ketosteroid reductase activity and expression by fetal rat osteoblasts
Thomas L McCarthy1, Richard B Hochberg, David C Labaree
1Department of Surgery, Section of Plastic Surgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA. thomas.mccarthy@yale.edu
The Journal of Biological Chemistry
|October 2, 2007
Summary
Rat osteoblasts possess enzymes that convert precursor compounds into potent sex hormone receptor agonists. This local metabolism in bone may influence skeletal health and hormone therapy effectiveness.
Area of Science:
- Endocrinology
- Molecular Biology
- Bone Biology
Background:
- Sex hormones influence bone metabolism through transcriptional regulation in osteoblasts.
- Some bone-sparing drugs target sex hormone receptors, but others have broader effects due to metabolism.
- Rat osteoblasts possess 3alpha-hydroxysteroid dehydrogenase activity, converting precursors to androgen receptor agonists.
Purpose of the Study:
- To investigate the presence and function of 3-ketosteroid reductase activity in rat osteoblasts.
- To elucidate the role of prostaglandin E2 (PGE2) in regulating this activity.
- To understand the molecular mechanisms underlying the regulation of 3-ketosteroid reductase.
Main Methods:
- Incubation of rat osteoblasts with tibolone and analysis of metabolites.
- Measurement of estrogen receptor alpha (ERα)-dependent gene promoter activity.
- Assessment of effects on TGF-beta/Smad and PGE2/Runx2 signaling pathways.
- Analysis of AKR1C9 gene promoter activity and mRNA expression.
- Investigation of the role of protein kinase A, C/EBPdelta, and PGE2 in AKR1C9 regulation.
Main Results:
- Rat osteoblasts efficiently convert tibolone to potent ERα agonists, primarily 3alpha-hydroxytibolone.
- Tibolone treatment induced ERα-dependent gene activity and enhanced TGF-beta and PGE2 signaling.
- Osteoblasts express 3-ketosteroid reductase AKR1C9, whose activity is regulated by PGE2.
- PGE2 increases AKR1C9 expression via C/EBPdelta binding to its promoter.
Conclusions:
- Rat osteoblasts possess significant and regulatable 3-ketosteroid reductase activity, in addition to 3alpha-hydroxysteroid dehydrogenase.
- These enzymatic activities allow local conversion of precursor compounds into potent steroid receptor agonists within bone.
- This local metabolic capacity may play a crucial role in bone homeostasis and the pharmacological effects of steroid modulators.
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