Abstract
BackgroundDespite their efficacy in the treatment of chronic inflammation, the prolonged application of therapeutic glucocorticoids (GCs) is limited by significant systemic side effects including glucocorticoid-induced osteoporosis (GIOP). 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a bi-directional enzyme that primarily activates GCs in vivo, regulating tissue-specific exposure to active GC. We aimed to determine the contribution of 11β-HSD1 to GIOP.MethodsWild type (WT) and 11β-HSD1 knockout (KO) mice were treated with corticosterone (100 μg/ml, 0.66% ethanol) or vehicle (0.66% ethanol) in drinking water over 4 weeks (six animals per group). Bone parameters were assessed by micro-CT, sub-micron absorption tomography and serum markers of bone metabolism. Osteoblast and osteoclast gene expression was assessed by quantitative RT-PCR.ResultsWild type mice receiving corticosterone developed marked trabecular bone loss with reduced bone volume to tissue volume (BV/TV), trabecular thickness (Tb.Th) and trabecular number (Tb.N). Histomorphometric analysis revealed a dramatic reduction in osteoblast numbers. This was matched by a significant reduction in the serum marker of osteoblast bone formation P1NP and gene expression of the osteoblast markers Alp and Bglap. In contrast, 11β-HSD1 KO mice receiving corticosterone demonstrated almost complete protection from trabecular bone loss, with partial protection from the decrease in osteoblast numbers and markers of bone formation relative to WT counterparts receiving corticosterone.ConclusionsThis study demonstrates that 11β-HSD1 plays a critical role in GIOP, mediating GC suppression of anabolic bone formation and reduced bone volume secondary to a decrease in osteoblast numbers. This raises the intriguing possibility that therapeutic inhibitors of 11β-HSD1 may be effective in preventing GIOP in patients receiving therapeutic steroids.
Highlights
Therapeutic glucocorticoids (GCs) show marked efficacy in the treatment of chronic inflammatory conditions
Deletion of 11β-HSD1 and inhibition of corticosterone generation in the bones of 11β-HSD1 KO mice was confirmed in ex vivo tibia biopsies, where corticosterone generation from DHC was significantly abrogated in 11β-HSD1 KO mice compared to Wild type (WT) animals (Fig. 1a)
Serum levels of corticosterone were significantly increased in both WT and 11β-HSD1 KO animals receiving corticosterone in drinking water relative to those receiving vehicle (WT, 41.2 ± 12.3 ng/ml versus WT + Cort, 479.6 ± 76.1 ng/ml, p < 0.01; 11β-HSD1 KO, 108.2 ± 72.2 ng/ml versus 11β-HSD1 KO + Cort, 329.5 ± 51.6 ng/ml, p < 0.05) (Fig. 1b) (Additional file 2)
Summary
Therapeutic glucocorticoids (GCs) show marked efficacy in the treatment of chronic inflammatory conditions. Glucocorticoid-induced osteoporosis (GIOP) is common in patients receiving therapeutic GCs with 30–50% of patients developing decreased bone mineral density and increased fracture risk within 6 months [4,5,6]. Several mechanisms have been proposed whereby GCs cause loss of bone mineral density and deterioration in bone architecture Chief amongst these is the direct inhibition of the osteoidforming osteoblasts within bone, as evidenced by a marked and rapid suppression of serum P1NP and osteocalcin in patients receiving the therapeutic GC prednisolone [7]. Despite their efficacy in the treatment of chronic inflammation, the prolonged application of therapeutic glucocorticoids (GCs) is limited by significant systemic side effects including glucocorticoid-induced osteoporosis (GIOP). We aimed to determine the contribution of 11β-HSD1 to GIOP
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