Expression and functional consequences of 11beta-hydroxysteroid dehydrogenase activity in human bone

Area of Science:

• Endocrinology
• Bone Biology
• Pharmacology

Background:

• Glucocorticoids are vital for skeletal development but harmful in excess.
• 11beta-hydroxysteroid dehydrogenase (11beta-HSD) isozymes regulate glucocorticoid activity by interconverting cortisol and cortisone.
• Previous studies indicated 11beta-HSD expression in fetal bone and osteosarcoma cells.

Purpose of the Study:

• To characterize 11beta-HSD expression and activity in adult human bone.
• To investigate the in vivo effect of 11beta-HSD inhibition on bone metabolism.

Main Methods:

• Enzyme activity assays, immunohistochemistry, and in situ hybridization were used to study 11beta-HSD isozymes in human bone tissue.
• Reverse transcription-polymerase chain reaction (RT-PCR) confirmed 11beta-HSD1 presence.
• A clinical study involved administering the 11beta-HSD inhibitor carbenoxolone to healthy volunteers.

Main Results:

• Adult human bone exhibits both 11beta-dehydrogenase and reductase activities, with significant interindividual variation in dehydrogenase activity.
• 11beta-HSD1 isozyme was localized to osteoblasts and osteoclasts, while 11beta-HSD2 was found at low levels in osteoblasts.
• Carbenoxolone administration significantly decreased urinary markers of bone resorption (pyridinoline and deoxypyridinoline) without affecting bone formation markers.

Conclusions:

• Local glucocorticoid metabolism by 11beta-HSD isozymes influences osteoblast and osteoclast sensitivity to glucocorticoids.
• Variations in 11beta-HSD expression and activity may contribute to individual susceptibility to glucocorticoid-induced osteoporosis.