Mice deficient in 11beta-hydroxysteroid dehydrogenase type 1 lack bone marrow adipocytes, but maintain normal bone formation.
Glucocorticoids (GCs) exert potent, but poorly characterized, effects on the skeleton. The cellular activity of GCs is regulated at a prereceptor level by 11beta-hydroxysteroid dehydrogenases (11betaHSDs). The type 1 isoform, which predominates in bone, functions as a reductase in intact cells and regenerates active cortisol (corticosterone) from circulating inert 11-keto forms. The aim of the present study was to investigate the role of this intracrine activation of GCs on normal bone physiology in vivo using mice deficient in 11betaHSD1 (HSD1(-/-)). The HSD1(-/-) mice exhibited no significant changes in cortical or trabecular bone mass compared with wild-type (Wt) mice. Aged HSD1(-/-) mice showed age-related bone loss similar to that observed in Wt mice. Histomorphometric analysis showed similar bone formation and bone resorption parameters in HSD1(-/-) and Wt mice. However, examination of bone marrow composition revealed a total absence of marrow adipocytes in HSD1(-/-) mice. Cells from Wt and HSD1(-/-) mice exhibited similar growth rates as well as similar levels of production of osteoblastic markers. The adipocyte-forming capacity of in vitro cultured bone marrow stromal cells and trabecular osteoblasts was similar in HSD1(-/-) and Wt mice. In conclusion, our results suggest that 11betaHSD1 amplification of intracellular GC actions in mice may be required for bone marrow adipocyte formation, but not for bone formation. The clinical relevance of this observation remains to be determined.
Justesen
Jeannette
J
University Department of Endocrinology and Metabolism, University Hospital of Aarhus, Denmark.
Mosekilde
Lis
L
Holmes
Megan
M
Stenderup
Karin
K
Gasser
Jürg
J
Mullins
John J
JJ
Seckl
Jonathan R
JR
Kassem
Moustapha
M
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000172:deficiency*; D017667:Adipocytes / Q000473:pathology*; D000375:Aging / Q000502:physiology; D000818:Animals; D001824:Body Constitution; D001835:Body Weight; D015519:Bone Density; D001853:Bone Marrow / Q000473:pathology*; D001842:Bone and Bones / Q000473:pathology; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D010006:Osteoblasts / Q000473:pathology; D010012:Osteogenesis; D010641:Phenotype; D012727:Sex Characteristics
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1