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Updated: Jun 14, 2026
A Novel in vivo Gene Transfer Technique and in vitro Cell Based Assays for the Study of Bone Loss in Musculoskeletal Disorders
Published on: June 8, 2014
Transgenic disruption of endogenous glucocorticoid signaling in osteoblasts does not alter long-term K/BxN serum
Tazio Maleitzke1,2,3,4, Edgar Wiebe5,6, Dörte Huscher7
1Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, NSW, Australia.
Background:
Disruption of glucocorticoid (GC) signaling in osteoblasts results in a marked attenuation of acute antibody-induced arthritis. The role of endogenous GCs in chronic inflammatory arthritis is however not fully understood. Here, we investigated the impact of endogenous GC signaling in osteoblasts on inflammation and bone integrity under chronic inflammatory arthritis by inactivating osteoblastic GC signaling in a long-term K/BxN serum transfer-induced induced arthritis (STIA) model.
Methods:
Intracellular GC signaling in osteoblasts was disrupted by transgenic (tg) overexpression of 11beta-hydroxysteroid dehydrogenase type 2 (11ß-HSD2). Inflammatory arthritis was induced in 5-week-old male tg mice and their wild type (WT) littermates by intraperitoneal (i.p.) injection of K/BxN serum while controls (CTRLs) received phosphate-buffered saline (PBS). In a first cohort, K/BxN STIA was allowed to abate until the endpoint of 42 days (STIA). To mimic rheumatic flares, a second cohort was additionally injected on days 14 and 28 with K/BxN serum (STIA boost). Arthritis severity was assessed daily by clinical scoring and ankle size measurements. Ankle joints were assessed histopathologically. Systemic effects of inflammation on long bone metabolism were analyzed in proximal tibiae by micro-computed tomography (μCT) and histomorphometry.
Results:
Acute arthritis developed in both tg and WT mice (STIA and STIA boost) and peaked around day 8. While WT STIA and tg STIA mice showed a steady decline of inflammation until day 42, WT STIA boost and tg STIA boost mice exhibited an arthritic phenotype over a period of 42 days. Clinical arthritis severity did not differ significantly between WT and tg mice, neither in the STIA nor in the STIA boost cohorts. Correspondingly, histological indices of inflammation, cartilage damage, and bone erosion showed no significant difference between WT and tg mice on day 42. Histomorphometry revealed an increased bone turnover in tg CTRL and tg STIA boost compared to WT CTRL and WT STIA boost animals, respectively.
Conclusions:
In contrast to the previously reported modulating effects of endogenous GC signaling in osteoblasts during acute K/BxN STIA, this effect seems to perish during the chronic inflammatory and resolution phase. These findings indicate that endogenous GC signaling in osteoblasts may mainly be relevant during acute and subacute inflammatory processes.
Insights
Glucocorticoid signaling in osteoblasts is crucial for acute arthritis but less so for chronic inflammatory conditions. This study found no significant difference in chronic arthritis severity or bone damage between normal and modified mice.
Area of Science:
- Endocrinology
- Immunology
- Rheumatology
Background:
- Glucocorticoid (GC) signaling in osteoblasts attenuates acute arthritis.
- The role of endogenous GCs in chronic inflammatory arthritis remains unclear.
- This study investigates osteoblast GC signaling in chronic arthritis models.
Purpose of the Study:
- To determine the impact of disrupted osteoblast GC signaling on inflammation and bone integrity in chronic arthritis.
- To evaluate the role of endogenous GCs in osteoblasts during long-term K/BxN serum transfer-induced arthritis (STIA).
Main Methods:
- Disrupted osteoblast GC signaling via transgenic overexpression of 11beta-hydroxysteroid dehydrogenase type 2 (11ß-HSD2).
- Induced chronic K/BxN serum transfer-induced arthritis (STIA) in transgenic and wild-type mice, with and without boosted serum injections.
- Assessed arthritis severity, joint histology, and long bone metabolism using clinical scoring, histopathology, and micro-computed tomography (μCT).
Main Results:
- Both transgenic and wild-type mice developed acute and chronic arthritis, with no significant difference in severity or histological damage.
- No significant differences in inflammation, cartilage damage, or bone erosion were observed between groups on day 42.
- Increased bone turnover was noted in transgenic mice under control and chronic boosted arthritis conditions compared to wild-type.
Conclusions:
- Osteoblast GC signaling's modulating effect on acute arthritis diminishes in chronic inflammatory phases.
- Endogenous GC signaling in osteoblasts appears primarily relevant for acute and subacute inflammatory processes.
- Disrupting osteoblast GC signaling did not alter chronic arthritis outcomes or bone integrity in this model.
