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Osteologie 2016; 25(04): 262-268
DOI: 10.1055/s-0037-1619028
Glukokortikoide und Knochen
Schattauer GmbH

Die molekularen Wirkmechanismen des Glukokortikoidrezeptors bei der Glukokortikoid-induzierten Osteoporose

Was wir von Mäusen gelernt habenMolecular mechanisms of the glucocorticoid receptor in glucocorticoid-induced osteoporosisLessons from the mouse
U. Baschant
1   Bereich Endokrinologie, Diabetes und Knochenerkrankungen, Medizinische Klinik III, Universitätsklinikum Dresden, Dresden
2   Zentrum für Gesundes Altern, Medizinische Fakultät der Technischen Universität Dresden, Dresden
,
M. Stein
3   Institu- te of Comparative Molecular Endocrinology (CME), Universität Ulm, Ulm
,
J. Tuckermann
3   Institu- te of Comparative Molecular Endocrinology (CME), Universität Ulm, Ulm
› Author Affiliations
Further Information

Publication History

eingereicht: 13 September 2016

angenommen: 27 September 2016

Publication Date:
23 December 2017 (online)

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Zusammenfassung

Die Glukokortikoid-induzierte Osteoporose (GIO) ist die häufigste Form der sekundären Osteoporose. Die molekularen Wirkmechanismen, über die Glukokortikoide (GC) zum Verlust von Knochenmasse führen, waren lange Zeit nicht bekannt. Genomweite Studien zum Glukokortikoidrezeptor (GR) sowie zellspezifische und funktionale Deletionen haben jedoch unser Verständnis von GC-Wirkmechanismen im Knochen revolutioniert. Der GR reguliert Genexpression als Ein zel-(Monomer) und Doppel-Molekül (Dimer) durch direkte und indirekte DNA-Bindung. Inzwischen ist funktionell erwiesen, dass vor allem direkte Effekte auf Osteoklasten, Osteoblasten und Osteozyten entscheidend sind. Hauptsächlich die Beeinträchtigung von Osteoblasten führt in der GIO zum Knochenschwund. Dies geschieht durch eine gesteigerte Apoptose, vermindertes Wachstum und vor allem gestörte Differenzierung von mesenchymalen Stammzellen. In hohen Dosen hemmen GC pro-osteogene Signalwege, wie etwa Wnt-Signale. GR-Monomer-abhängige Genexpression scheint hierbei maßgebend zu sein. Aktuelle Herausforderungen in der GIO-Forschung sind das Verständnis der physiologischen, anabolen GC-Funktion, die genaue Definition von Differenzierungsstadien, die sensibel auf pharmakologisch-dosierte GC reagieren, sowie die Identifizierung von neuen Zielstrukturen, die es erlauben, die knochenschä-digenden Wirkungen von GC zu überwinden.

Summary

Glucocorticoid-induced osteoporosis (GIO) is the most common form of secondary osteo -porosis. As glucocorticoids (GC) act on most tissues, the cellular and molecular mechanisms of GC induced bone loss were not known for a long time. Genome wide studies of DNA binding by the GC receptor, the GR, and cell-type specific and function-selective deletions of the GR have recently revolutionized our understanding of GC action in bone. After nuclear translocation the GR regulates gene expression by binding as a monomer or dimer directly or indirectly to DNA. There are now multiple lines of evidence that GC actions on bone are mainly mediated directly by the bone cells i. e. osteoclasts, osteoblasts and osteocytes. GC treatment can induce osteoclast activity and cause high rates of bone resorption but the effect of GR signaling on os teoclast development and function still remains controversial. Osteocytes have been shown to be very sensitive to GC-induced apoptosis. Nonetheless, the major cause of bone loss in GIO appears to be the impairment of osteoblast function which in fact takes place at several levels. GC induce apoptosis and inhibit osteoblast proliferation. Most importantly they also inhibit the differentiation of osteoblasts from mesenchymal progenitor cells. GC lead to the enhancement of adipogenesis at the cost of osteoblast development. Whether this takes place at the same level of progenitor cells still remains to be elucidated, however. High dose GC exposure of bone cells leads to interference with pro-osteogenic signaling, such as the Wnt pathway. GR monomer-dependent gene expression programs seem to be decisive here. miRNAs have also been shown to influence the bone integrity but at least in GIO they appear to play a minor role. Despite substantial progress of understanding molecular mechanisms underlying GIO, some questions remain unanswered. Current challenges in GIO research are i) the understanding of physiological anabolic effects of low dose GCs, ii) the clear definition of the osteoblast and osteoclast differentiation stages that are vul nerable to pharmacological GCs in vivo and iii) the identification of novel drug targets, enhancing osteoblast function to overcome the deleterious effects of GCs on bone. Novel high-throughput screening methods for primary cells and facilitated genetic manipulation for rodent models offer a promising outlook for this challenging task.

Schlüsselwörter

Glukokortikoidrezeptor - Glukokortikoid-induzierte Osteoporose - Osteoblast - Osteoklast - Osteozyt

Keywords

Glucocorticoid receptor - glucocorticoid-induced osteoporosis - osteoblast - osteoclast - osteocyte
 

  • Literatur

  • 1 Van Staa TP, Leufkens HG, Abenhaim L. et al. Use of oral corticosteroids and risk of fractures. Journal of bone and mineral research 2000; 15 (06) 993-1000.
    CrossrefPubMedGoogle Scholar
  • 2 Canalis E, Mazziotti G, Giustina A, Bilezikian JP. Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporosis International 2007; 18 (10) 1319-1328.
    CrossrefPubMedGoogle Scholar
  • 3 Rauch A, Seitz S, Baschant U. et al. Glucocorticoids suppress bone formation by attenuating osteoblast differentiation via the monomeric glucocorticoid receptor. Cell Metab 2010; 11 (06) 517-531.
    CrossrefPubMedGoogle Scholar
  • 4 O’Brien CA, Jia D, Plotkin LI. et al. Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinology 2004; 145 (04) 1835-1841.
    CrossrefPubMedGoogle Scholar
  • 5 Frenkel B, White W, Tuckermann J. Glucocorticoid-Induced Osteoporosis. Adv Exp Med Biol 2015; 872: 179-215.
    PubMedGoogle Scholar
  • 6 Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC. Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Invest 1998; 102 (02) 274-282.
    CrossrefPubMedGoogle Scholar
  • 7 De Bosscher K, Beck IM, Ratman D. et al. Activation of the Glucocorticoid Receptor in Acute Inflammation: the SEDIGRAM Concept. Trends in Pharmacological Sciences 2016; 37 (01) 4-16.
    CrossrefPubMedGoogle Scholar
  • 8 John S, Sabo PJ, Thurman RE. et al. Chromatin accessibility pre-determines glucocorticoid receptor binding patterns. Nat Genet 2011; 43 (03) 264-268.
    CrossrefPubMedGoogle Scholar
  • 9 Uhlenhaut NH, Barish GD, Yu RT. et al. Insights into Negative Regulation by the Glucocorticoid Receptor from Genome-Wide Profiling of Inflammatory Cistromes. Molecular cell 2013; 49 (01) 158-171.
    CrossrefPubMedGoogle Scholar
  • 10 Lim HW, Uhlenhaut NH, Rauch A. et al. Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo. Genome Res 2015; 25 (06) 836-844.
    CrossrefPubMedGoogle Scholar
  • 11 Baschant U, Tuckermann J. The role of the glucocorticoid receptor in inflammation and immunity. The Journal of Steroid Biochemistry and Molecular Biology 2010; 120 2-3 69-75.
    CrossrefPubMedGoogle Scholar
  • 12 Vettorazzi S, Bode C, Dejager L. et al. Glucocorticoids limit acute lung inflammation in concert with inflammatory stimuli by induction of SphK1. Nature communications 2015; 06: 7796.
    CrossrefPubMedGoogle Scholar
  • 13 Baschant U, Frappart L, Rauchhaus U. et al. Glucocorticoid therapy of antigen-induced arthritis depends on the dimerized glucocorticoid receptor in T cells. Proceedings of the National Academy of Sciences of the United States of America 2011; 108 (48) 19317-19322.
    CrossrefPubMedGoogle Scholar
  • 14 Hübner S, Dejager L, Libert C, Tuckermann JP. The glucocorticoid receptor in inflammatory processes: transrepression is not enough. Biological chemistry 2015; 396 (11) 1223-1231.
    PubMedGoogle Scholar
  • 15 Hofbauer LC, Gori F, Riggs BL. et al. Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid-induced os- teoporosis. Endocrinology 1999; 140 (10) 4382-4389.
    CrossrefPubMedGoogle Scholar
  • 16 Rauner M, Goettsch C, Stein N. et al. Dissociation of osteogenic and immunological effects by the selective glucocorticoid receptor agonist, compound A, in human bone marrow stromal cells. Endocrinology 2011; 152 (01) 103-112.
    CrossrefPubMedGoogle Scholar
  • 17 Piemontese M, Xiong J, Fujiwara Y. et al. Cortical bone loss caused by glucocorticoid excess requires RANKL production by osteocytes and is associated with reduced OPG expression in mice. American journal of physiology Endocrinology and metabolism. 2016 ajpendo 00219 2016..
    PubMedGoogle Scholar
  • 18 Hofbauer LC, Zeitz U, Schoppet M. et al. Prevention of glucocorticoid-induced bone loss in mice by inhibition of RANKL. Arthritis Rheum 2009; 60 (05) 1427-1437.
    CrossrefPubMedGoogle Scholar
  • 19 Jia D, O’Brien CA, Stewart SA. et al. Glucocorticoids Act Directly on Osteoclasts to Increase Their Life Span and Reduce Bone Density. Endocrinology 2006; 147 (12) 5592-5599.
    CrossrefPubMedGoogle Scholar
  • 20 Kim H-J, Zhao H, Kitaura H. et al. Glucocorticoids suppress bone formation via the osteoclast. The Journal of Clinical Investigation 2006; 116 (08) 2152-2160.
    CrossrefPubMedGoogle Scholar
  • 21 Hong JM, Teitelbaum SL, Kim TH. et al. Calpain-6, a target molecule of glucocorticoids, regulates osteoclastic bone resorption via cytoskeletal organiz- ation and microtubule acetylation. J Bone Miner Res 2011; 26 (03) 657-665.
    CrossrefPubMedGoogle Scholar
  • 22 Conaway HH, Henning P, Lie A. et al. Activation of dimeric glucocorticoid receptors in osteoclast progenitors potentiates RANKL induced mature osteoclast bone resorbing activity. Bone 2016; 93: 43-54.
    CrossrefPubMedGoogle Scholar
  • 23 Søe K, Delaissé J-M. Glucocorticoids maintain human osteoclasts in the active mode of their resorption cycle. Journal of bone and mineral research 2010; 25 (10) 2184-2192.
    CrossrefPubMedGoogle Scholar
  • 24 Hartmann K, Koenen M, Schauer S. et al. Molecular Actions of Glucocorticoids in Cartilage and Bone During Health, Disease, and Steroid Therapy. Physiol Rev 2016; 96 (02) 409-447.
    CrossrefPubMedGoogle Scholar
  • 25 Horsch K, de Wet H, Schuurmans MM. et al. Mitogen-Activated Protein Kinase Phosphatase 1/Dual Specificity Phosphatase 1 Mediates Glucocorticoid Inhibition of Osteoblast Proliferation. Molecular endocrinology (Baltimore, Md) 2007; 21 (12) 2929-2940.
    CrossrefPubMedGoogle Scholar
  • 26 Conradie MM, Cato AC, Ferris WF. et al. MKP-1 knockout does not prevent glucocorticoid-induced bone disease in mice. Calcif Tissue Int 2011; 89 (03) 221-227.
    CrossrefPubMedGoogle Scholar
  • 27 Suchacki KJ, Cawthorn WP, Rosen CJ. Bone marrow adipose tissue: formation, function and regulation. Current Opinion in Pharmacology 2016; 28: 50-56.
    CrossrefPubMedGoogle Scholar
  • 28 Asada M, Rauch A, Shimizu H. et al. DNA binding-dependent glucocorticoid receptor activity promotes adipogenesis via Kruppel-like factor 15 gene expression. Lab Invest 2011; 91 (02) 203-215.
    CrossrefPubMedGoogle Scholar
  • 29 Ono N, Ono W, Nagasawa T, Kronenberg HM. A subset of chondrogenic cells provides early mesenchymal progenitors in growing bones. Nature Cell Biology 2014; 16 (12) 1157-1167.
    CrossrefPubMedGoogle Scholar
  • 30 Worthley DL, Churchill M, Compton JT. et al. Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential. Cell 2015; 160 1-2 269-284.
    CrossrefPubMedGoogle Scholar
  • 31 Chan CK, Seo EY, Chen JY. et al. Identification and specification of the mouse skeletal stem cell. Cell 2015; 160 1-2 285-298.
    CrossrefPubMedGoogle Scholar
  • 32 Bianco P, Cao X, Frenette PS. et al. The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nature Publishing Group 2013; 19 (01) 35-42.
    Google Scholar
  • 33 Matic I, Matthews BG, Wang X. et al. Quiescent Bone Lining Cells Are a Major Source of Osteoblasts During Adulthood. Stem Cells. 2016 Aug 10. [Epub ahead of print].
    PubMedGoogle Scholar
  • 34 Mak W, Shao X, Dunstan CR, Seibel MJ, Zhou H. Biphasic glucocorticoid-dependent regulation of Wnt expression and its inhibitors in mature osteoblastic cells. Calcif Tissue Int 2009; 85 (06) 538-545.
    CrossrefPubMedGoogle Scholar
  • 35 Wang FS, Ko JY, Yeh DW. et al. Modulation of Dickkopf-1 attenuates glucocorticoid induction of osteoblast apoptosis, adipocytic differentiation, and bone mass loss. Endocrinology 2008; 149 (04) 1793-1801.
    CrossrefPubMedGoogle Scholar
  • 36 Hayashi K, Yamaguchi T, Yano S. et al. BMP/Wnt antagonists are upregulated by dexamethasone in osteoblasts and reversed by alendronate and PTH: potential therapeutic targets for glucocorticoid-induced osteoporosis. Biochem Biophys Res Commun 2009; 379 (02) 261-266.
    CrossrefPubMedGoogle Scholar
  • 37 Liu P, Baumgart M, Groth M. et al. Dicer ablation in osteoblasts by Runx2 driven cre-loxP recombination affects bone integrity, but not glucocorticoid-induced suppression of bone formation. Sci Rep 2016; 06: 32112.
    CrossrefPubMedGoogle Scholar
  • 38 Wang F-S, Chuang P-C, Chung P-C. et al. MicroRNA-29a protects against glucocorticoid-induced bone loss and fragility in rats by orchestrating bone acquisition and resorption. Arthritis & Rheumatism 2013; 65 (06) 1530-1540.
    CrossrefPubMedGoogle Scholar
  • 39 Dallas SL, Prideaux M, Bonewald LF. The Osteocyte: An Endocrine Cell … and More. Endocrine Reviews 2013; 34 (05) 658-690.
    CrossrefPubMedGoogle Scholar
  • 40 Plotkin LI, Manolagas SC, Bellido T. Glucocorticoids induce osteocyte apoptosis by blocking focal adhesion kinase-mediated survival. Evidence for inside-out signaling leading to anoikis. J Biol Chem 2007; 282 (33) 24120-24130.
    CrossrefPubMedGoogle Scholar
  • 41 Jia J, Yao W, Guan M. et al. Glucocorticoid dose determines osteocyte cell fate. The FASEB Journal 2011; 25 (10) 3366-3376.
    CrossrefPubMedGoogle Scholar
  • 42 Yao W, Cheng Z, Busse C. et al. Glucocorticoid excess in mice results in early activation of osteoclastogenesis and adipogenesis and prolonged suppression of osteogenesis: A longitudinal study of gene expression in bone tissue from glucocorticoid-treated mice. Arthritis & Rheumatism 2008; 58 (06) 1674-1686.
    CrossrefPubMedGoogle Scholar
  • 43 van Lierop AH, van der Eerden AW, Hamdy NA. et al. Circulating sclerostin levels are decreased in patients with endogenous hypercortisolism and increase after treatment. J Clin Endocrinol Metab 2012; 97 (10) E1953-E1957.
    CrossrefPubMedGoogle Scholar
  • 44 Hay E, Bouaziz W, Funck-Brentano T, Cohen-Solal M. Sclerostin and Bone Aging: A Mini-Review. Gerontology. 2016 May 14. [Epub ahead of print].
    PubMedGoogle Scholar
  • 45 Yao W, Dai W, Jiang L. et al. Sclerostin-antibody treatment of glucocorticoid-induced osteoporosis maintained bone mass and strength. Osteoporos Int 2016; 27 (01) 283-294.
    CrossrefPubMedGoogle Scholar
  • 46 Sato AY, Cregor M, Delgado-Calle J. et al. Protection from Glucocorticoid-Induced Osteoporosis by Anti-Catabolic Signaling in the Absence of Sost/Sclerostin. J Bone Miner Res. 2016 May 10. [Epub ahead of print].
    PubMedGoogle Scholar
  • 47 Saag KG, Shane E, Boonen S. et al. Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J Med 2007; 357 (20) 2028-2039.
    CrossrefPubMedGoogle Scholar
  • 48 Brixen KT, Christensen PM, Ejersted C, Langdahl BL. Teriparatide (biosynthetic human parathyroid hormone 1-34): a new paradigm in the treatment of osteoporosis. Basic Clin Pharmacol Toxicol 2004; 94 (06) 260-270.
    CrossrefPubMedGoogle Scholar
  • 49 Kroll T, Schmidt D, Schwanitz G. et al. High-Content Microscopy Analysis of Subcellular Structures: Assay Development and Application to Focal Adhesion Quantification. Curr Protoc Cytom 2016; 77: 12431-12434.
    Google Scholar