Transgenic disruption of endogenous glucocorticoid signaling in osteoblasts does not alter long-term K/BxN serum transfer-induced arthritis
Abstract 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 signalin...
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| Format: | Article |
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BMC
2023-08-01
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| Series: | Arthritis Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13075-023-03112-9 |
| _version_ | 1797557438966136832 |
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| author | Tazio Maleitzke Edgar Wiebe Dörte Huscher Cornelia M. Spies Jinwen Tu Timo Gaber Yu Zheng Frank Buttgereit Markus J. Seibel Hong Zhou |
| author_facet | Tazio Maleitzke Edgar Wiebe Dörte Huscher Cornelia M. Spies Jinwen Tu Timo Gaber Yu Zheng Frank Buttgereit Markus J. Seibel Hong Zhou |
| author_sort | Tazio Maleitzke |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-10T17:17:03Z |
| format | Article |
| id | doaj.art-39e36f88625d46b9843de9f0a12cf76c |
| institution | Directory Open Access Journal |
| issn | 1478-6362 |
| language | English |
| last_indexed | 2024-03-10T17:17:03Z |
| publishDate | 2023-08-01 |
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| series | Arthritis Research & Therapy |
| spelling | doaj.art-39e36f88625d46b9843de9f0a12cf76c2023-11-20T10:27:24ZengBMCArthritis Research & Therapy1478-63622023-08-0125111210.1186/s13075-023-03112-9Transgenic disruption of endogenous glucocorticoid signaling in osteoblasts does not alter long-term K/BxN serum transfer-induced arthritisTazio Maleitzke0Edgar Wiebe1Dörte Huscher2Cornelia M. Spies3Jinwen Tu4Timo Gaber5Yu Zheng6Frank Buttgereit7Markus J. Seibel8Hong Zhou9Bone Research Program, ANZAC Research Institute, University of SydneyBone Research Program, ANZAC Research Institute, University of SydneyInstitute of Biometry and Clinical Epidemiology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin Institute of HealthBone Research Program, ANZAC Research Institute, University of SydneyBone Research Program, ANZAC Research Institute, University of SydneyDepartment of Rheumatology and Clinical Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität Zu BerlinBone Research Program, ANZAC Research Institute, University of SydneyDepartment of Rheumatology and Clinical Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität Zu BerlinBone Research Program, ANZAC Research Institute, University of SydneyBone Research Program, ANZAC Research Institute, University of SydneyAbstract 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.https://doi.org/10.1186/s13075-023-03112-911ß-HSD2CortisolCortisoneRheumatoid arthritisAntibodyJoint inflammation |
| spellingShingle | Tazio Maleitzke Edgar Wiebe Dörte Huscher Cornelia M. Spies Jinwen Tu Timo Gaber Yu Zheng Frank Buttgereit Markus J. Seibel Hong Zhou Transgenic disruption of endogenous glucocorticoid signaling in osteoblasts does not alter long-term K/BxN serum transfer-induced arthritis Arthritis Research & Therapy 11ß-HSD2 Cortisol Cortisone Rheumatoid arthritis Antibody Joint inflammation |
| title | Transgenic disruption of endogenous glucocorticoid signaling in osteoblasts does not alter long-term K/BxN serum transfer-induced arthritis |
| title_full | Transgenic disruption of endogenous glucocorticoid signaling in osteoblasts does not alter long-term K/BxN serum transfer-induced arthritis |
| title_fullStr | Transgenic disruption of endogenous glucocorticoid signaling in osteoblasts does not alter long-term K/BxN serum transfer-induced arthritis |
| title_full_unstemmed | Transgenic disruption of endogenous glucocorticoid signaling in osteoblasts does not alter long-term K/BxN serum transfer-induced arthritis |
| title_short | Transgenic disruption of endogenous glucocorticoid signaling in osteoblasts does not alter long-term K/BxN serum transfer-induced arthritis |
| title_sort | transgenic disruption of endogenous glucocorticoid signaling in osteoblasts does not alter long term k bxn serum transfer induced arthritis |
| topic | 11ß-HSD2 Cortisol Cortisone Rheumatoid arthritis Antibody Joint inflammation |
| url | https://doi.org/10.1186/s13075-023-03112-9 |
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