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      Glucocorticoid-Induced Autophagy in Osteocytes

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          Abstract

          Glucocorticoid (GC) therapy is the most frequent cause of secondary osteoporosis. In this study we have demonstrated that GC treatment induced the development of autophagy, preserving osteocyte viability. GC treatment resulted in an increase in autophagy markers and the accumulation of autophagosome vacuoles in vitro and in vivo promoted the onset of the osteocyte autophagy, as determined by expression of autophagy markers in an animal model of GC-induced osteoporosis. An autophagy inhibitor reversed the protective effects of GCs. The effects of GCs on osteocytes were in contrast to tumor necrosis factor α (TNF-α), which induced apoptosis but not autophagy. Together this study reveals a novel mechanism for the effect of GC on osteocytes, shedding new insight into mechanisms responsible for bone loss in patients receiving GC therapy. © 2010 American Society for Bone and Mineral Research.

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          How to interpret LC3 immunoblotting.

          Noboru Mizushima, Tamotsu Yoshimori (2007)
          Microtubule-associated protein light chain 3 (LC3) is now widely used to monitor autophagy. One approach is to detect LC3 conversion (LC3-I to LC3-II) by immunoblot analysis because the amount of LC3-II is clearly correlated with the number of autophagosomes. However, LC3-II itself is degraded by autophagy, making interpretation of the results of LC3 immunoblotting problematic. Furthermore, the amount of LC3 at a certain time point does not indicate autophagic flux, and therefore, it is important to measure the amount of LC3-II delivered to lysosomes by comparing LC3-II levels in the presence and absence of lysosomal protease inhibitors. Another problem with this method is that LC3-II tends to be much more sensitive to be detected by immunoblotting than LC3-I. Accordingly, simple comparison of LC3-I and LC3-II, or summation of LC3-I and LC3-II for ratio determinations, may not be appropriate, and rather, the amount of LC3-II can be compared between samples.
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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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              Monodansylcadaverine (MDC) is a specific in vivo marker for autophagic vacuoles.

              Theodore Elsasser, A Biederbick, Gunther Kern (1994)
              We report the use of the autofluorescent compound monodansylcadaverine (MDC) for in vivo labeling of autophagic vacuoles. When applied to various cell types (PaTu 8902, MDCK I, PC12, AR4-2J, WI-38) in culture, spherical structures were observed by fluorescence microscopy, predominantly located in the perinuclear region. Only PC12 and WI-38 cells had some of these labeled structures in their filopodiae. Dose-response experiments with PaTu 8902 showed that the optimal concentration for in vivo labeling was 0.05 to 0.1 mM, while cells detached and disintegrated, when MDC concentration exceeded 0.1 mM. After incubation with MDC and subcellular fractionations of PaTu 8902 cells on sucrose density gradients, a narrow fluorescence peak at 20 to 26% sucrose concentration equal to densities of about 1.081 to 1.108 g/cm3 was observed. Ultrastructural analysis of these fractions revealed autophagic vacuoles in different stages of their development. To investigate whether endosomal compartments were also labeled by MDC, we coincubated PaTu 8902 cells with MDC and the fluid-phase markers, RITC-dextran and ferritin, respectively. Fluorescence measurements after subcellular fractionations as well as fine structural analysis indicated that MDC-labeled autophagic vacuoles did not contain fluid-phase markers and were spatially separated from endosomal compartments. We further could demonstrate, after subcellular fractionation procedures, that MDC-labeled organelles contained the lysosomal enzymes acid phosphatase and the mature form of cathepsin D. Membrane markers of rough endoplasmic reticulum (TRAM and sec61 beta), and for smooth endoplasmic reticulum (cytochrome P450) were not detected in the same fractions. These results indicate that MDC accumulates as a selective fluorescent marker for autophagic vacuoles under in vivo conditions and is not present in the early and late endosome.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Bone Miner Res
                Journal ID (publisher-id): jbmr
                Title: Journal of Bone and Mineral Research
                Publisher: Wiley Subscription Services, Inc., A Wiley Company
                ISSN (Print): 0884-0431
                ISSN (Electronic): 1523-4681
                Publication date (Print): November 2010
                Publication date (Electronic): 18 June 2010
                Volume: 25
                Issue: 11
                Pages: 2479-2488
                Affiliations
                [1 ]simpleDepartment of Biochemistry, University of Texas Health Science Center San Antonio, TX, USA
                [2 ]simpleDepartment of Orthodontics, University of Texas Health Science Center San Antonio, TX, USA
                [3 ]simpleCenter for Healthy Aging, Internal Medicine, University of California at Davis Medical Center Sacramento, CA, USA
                [4 ]simpleDepartment of Oral Biology, School of Dentistry, University of Missouri Kansas City, MO, USA
                [5 ]simpleDepartment of Neurobiology, Morehouse School of Medicine Atlanta, GA, USA
                Author notes
                Address correspondence to: Jean X Jiang, PhD, Department of Biochemistry, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA. E-mail: jiangj@ 123456uthscsa.edu
                Article
                DOI: 10.1002/jbmr.160
                PMC ID: 3179284
                PubMed ID: 20564240
                SO-VID: 9b698dea-ca13-4d8a-85d1-26a27a4828fd
                Copyright © Copyright © 2010 American Society for Bone and Mineral Research
                License:

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                History
                Date received : 13 July 2009
                Date revision received : 05 April 2010
                Date accepted : 04 June 2010
                Categories
                Subject: Original Article

                ScienceOpen disciplines: Human biology
                Keywords: autophagy,viability,osteocyte,glucocorticoid
                Data availability:
                ScienceOpen disciplines: Human biology
                Keywords: autophagy, viability, osteocyte, glucocorticoid

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