Osteoblast-specific 11β-HSD1 overexpression enhances bone mass without inducing systemic side effects

Introduction: Glucocorticoids (GCs) play a central role in regulating inflammation and immune responses and are therefore widely used to treat inflammatory and degenerative bone diseases. However, chronic systemic GC exposure is associated with substantial adverse effects, including impaired bone formation, increased bone resorption, and metabolic disturbances. These limitations underscore the need for strategies that preserve the anti-inflammatory benefits of GCs while minimizing their detrimental systemic impact. Local GC metabolism within the cells is mainly governed by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive GCs into their active forms and thereby amplifies intracellular GC signaling. While excessive systemic GC activity compromises skeletal integrity, targeted modulation of 11β-HSD1 within specific bone cell populations may enhance local GC actions that support bone formation without inducing whole-body side effects. Methods : Therefore, we generated a mouse model enabling osteoblast-specific enhancement of GC signaling through targeted overexpression of 11β-HSD1. Overexpression was validated at both the gene and protein levels using qPCR and Western blot analyses. Local corticosterone concentrations were quantified by LC/MS to confirm increased GC availability. Bone metabolism and structural changes were assessed using µCT imaging and histological evaluation. Results : Osteoblast-specific 11β-HSD1 overexpression resulted in increased HSD11B1 expression restricted to osteoblasts, with elevated corticosterone levels detected exclusively in bone (1.5-fold, p5-fold, p