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      Glucocorticoid Receptor and Sequential P53 Activation by Dexamethasone Mediates Apoptosis and Cell Cycle Arrest of Osteoblastic MC3T3-E1 Cells

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          Abstract

          Glucocorticoids play a pivotal role in the proliferation of osteoblasts, but the underlying mechanism has not been successfully elucidated. In this report, we have investigated the molecular mechanism which elucidates the inhibitory effects of dexamethasone on murine osteoblastic MC3T3-E1 cells. It was found that the inhibitory effects were largely attributed to apoptosis and G1 phase arrest. Both the cell cycle arrest and apoptosis were dependent on glucocorticoid receptor (GR), as they were abolished by GR blocker RU486 pre-treatment and GR interference. G1 phase arrest and apoptosis were accompanied with a p53-dependent up-regulation of p21 and pro-apoptotic genes NOXA and PUMA. We also proved that dexamethasone can’t induce apoptosis and cell cycle arrest when p53 was inhibited by p53 RNA interference. These data demonstrate that proliferation of MC3T3-E1 cell was significantly and directly inhibited by dexamethasone treatment via aberrant GR activation and subsequently P53 activation.

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          Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength.

          C. O’Brien, Dan Jia, Teresita Bellido … (2004)
          Whether the negative impact of excess glucocorticoids on the skeleton is due to direct effects on bone cells, indirect effects on extraskeletal tissues, or both is unknown. To determine the contribution of direct effects of glucocorticoids on osteoblastic/osteocytic cells in vivo, we blocked glucocorticoid action on these cells via transgenic expression of 11beta-hydroxysteroid dehydrogenase type 2, an enzyme that inactivates glucocorticoids. Osteoblast/osteocyte-specific expression was achieved by insertion of the 11beta-hydroxysteroid dehydrogenase type 2 cDNA downstream from the osteoblast-specific osteocalcin promoter. The transgene did not affect normal bone development or turnover as demonstrated by identical bone density, strength, and histomorphometry in adult transgenic and wild-type animals. Administration of excess glucocorticoids induced equivalent bone loss in wild-type and transgenic mice. As expected, cancellous osteoclasts were unaffected by the transgene. However, the increase in osteoblast apoptosis that occurred in wild-type mice was prevented in transgenic mice. Consistent with this, osteoblasts, osteoid area, and bone formation rate were significantly higher in glucocorticoid-treated transgenic mice compared with glucocorticoid-treated wild-type mice. Glucocorticoid-induced osteocyte apoptosis was also prevented in transgenic mice. Strikingly, the loss of vertebral compression strength observed in glucocorticoid-treated wild-type mice was prevented in the transgenic mice, despite equivalent bone loss. These results demonstrate for the first time that excess glucocorticoids directly affect bone forming cells in vivo. Furthermore, our results suggest that glucocorticoid-induced loss of bone strength results in part from increased death of osteocytes, independent of bone loss.
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            Nationwide Epidemiologic Survey of Idiopathic Osteonecrosis of the Femoral Head

            Wakaba Fukushima, Mikihiro Fujioka, Toshikazu Kubo … (2010)
            Background Although numerous studies describe the clinical characteristics of idiopathic osteonecrosis of the femoral head (ONFH) in specific study populations, these have not been confirmed in countrywide studies. Questions/purposes We therefore determined: (1) the annual number of patients seeking medical care and number of patients newly diagnosed; and (2) the distribution of the age and gender of the patients, potential causative factors, severity of the disease, and operative procedures performed. Patients and Methods We conducted a nationwide epidemiologic survey in 2005. The survey included all orthopaedic departments in Japan by stratified random sampling according to the number of beds. Results The number of patients who sought medical care for idiopathic ONFH during 2004 was estimated to be 11,400 (95% confidence interval, 10,100–12,800). We obtained clinical information from 1502 of these patients. The peak in age distribution occurred in the 40s. Potential causative factors were systemic steroid administration (51%) and habitual alcohol use (31%). Hip replacement was the most frequently performed procedure (65%). Among patients with a history of systemic steroid administration, systemic lupus erythematosus was reported most frequently (31%) as the underlying disease. Among patients younger than 40 years, steroid use was the most prominent potential causative factor (60%), and hip replacement frequently was performed (45%). A greater proportion of patients with no history of steroid or alcohol use was observed among patients 65 years or older (41%). Conclusions In addition to the disease burden of idiopathic ONFH in Japan, our results confirmed the importance of developing preventive and treatment strategies, especially among the younger population. Level of Evidence Level IV, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.
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              Glucocorticoid-induced leucine zipper (GILZ): a new important mediator of glucocorticoid action.

              Carlo Riccardi, Emira Ayroldi (2009)
              Glucocorticoids (GCs) represent the mainstay of current anti-inflammatory and immunosuppressive strategies, mediating effects that mostly result in transcriptional regulation of glucocorticoid receptor target genes. A variety of actions are tied together in the response to GC treatment. Dissecting the beneficial from the detrimental actions in GC therapy is a major challenge in basic research, raising the critical issue of whether a single target gene or gene family might eventually be linked to a specific GC function. Glucocorticoid-induced leucine zipper (GILZ) was originally discovered in studies aimed at characterizing genes targeted by dexamethasone. The first suggestion that GILZ plays an important role in GC immunomodulation came from observations of GILZ up-regulation by GCs, mainly in lymphoid organs, and inhibition of anti-CD3-induced activation and apoptosis. The identification of GILZ interaction with and inhibition of NF-kappaB provided a first molecular mechanistic basis for explaining GILZ effects on T cells. Subsequently, other GILZ targets have been identified, including AP-1, Raf-1, and Ras, all involved in GC effects. The finding that GILZ silencing abrogates the antiproliferative activity of dexamethasone and reduces GC inhibition of cytokine-induced COX-2 expression clearly gained GILZ a distinguished reputation within the critical mediators of GC effects. The multiple functions of GILZ and their potential biological relevance are here reviewed.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2012
                Publication date (Electronic): 14 June 2012
                Volume: 7
                Issue: 6
                Electronic Location Identifier: e37030
                Affiliations
                [1]Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
                Rush University Medical Center, United States of America
                Author notes

                Conceived and designed the experiments: XW ZW. Performed the experiments: Hui Li WQ YB. Analyzed the data: QZ BF. Wrote the paper: Hui Li Huihua Li.

                Article
                Publisher ID: PONE-D-11-25158
                DOI: 10.1371/journal.pone.0037030
                PMC ID: 3375272
                PubMed ID: 22719835
                SO-VID: 5de98eff-f379-4c7c-84b6-1a1cae60bdd7
                Copyright © Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 9 December 2011
                Date accepted : 11 April 2012
                Page count
                Pages: 10
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Anatomy and Physiology
                Subject: Cell Physiology
                Subject: Molecular Cell Biology
                Subject: Signal Transduction
                Subject: Mechanisms of Signal Transduction
                Subject: Cell Death
                Subject: Cell Division
                Subject: Cell Growth
                Subject: Gene Expression
                Subject: Chemistry
                Subject: Chemical Biology
                Subject: Medicine
                Subject: Surgery
                Subject: Orthopedic Surgery
                Subject: Joint Replacement Surgery

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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