An Overview of the Role of Glucocorticoids in the Pathophysiology of Endocrine Disorders Glucocorticoids and Osteoporosis
GC treatment is associated with rapid bone loss, and fractures are a common side effect of long-term GC therapy.96
Bone remodelling is
dependent on the absorption of old bone matrix by osteoclasts, followed by the generation of new bone matrix by osteoblasts that subsequently enter the resorptive lacuna. GCs interfere with bone matrix formation via induction of osteoblast apoptosis via activation of caspase-3, in addition to decreasing the number of osteoblast precursor cells available for differentiation.97
Chronic GC treatment
induces the expression of macrophage colony-stimulating factor (M- CSF) and receptor activator of NF-κB ligand (RANKL), both of which are necessary for osteoclast development. GCs also increase osteoclast maturation and survival, which is classically associated with increased bone resorption and rapid loss of trabecular bone.98,99 However, recent studies suggest that osteoclasts induce a more complex effect on bone remodelling. Osteoclasts act to resorb old bone, an action that requires cytoskeletal organisation. As osteoclasts absorb the old bone matrix, they release factors that promote the movement of osteoblasts into the resorptive lacuna, which then act to synthesise new bone. Long-term GC therapy suppresses specific osteoclast functions related to cytoskeletal organisation and recruitment of osteoblasts, and therefore greatly reduces new bone formation.100
1. Delbende C, Delarue C, Lefebvre H, et al., Glucocorticoids, transmitters and stress, Br J Psychiatry Suppl, 1992;15:24–35.
2. Reyes TM, Walker JR, DeCino C, et al., Categorically distinct acute stressors elicit dissimilar transcriptional profiles in the paraventricular nucleus of the hypothalamus, J Neurosci, 2003;23:5607–16.
3. Crown A, Lightman S, Why is the management of glucocorticoid deficiency still controversial: a review of the literature, Clin Endocrinol (Oxf), 2005;63:483–92.
4. Bergendahl M, Iranmanesh A, Mulligan T, Veldhuis JD, Impact of age on cortisol secretory dynamics basally and as driven by nutrient-withdrawal stress, J Clin Endocrinol Metab, 2000;85:2203–14.
5. Kerrigan JR, Veldhuis JD, Leyo SA, et al., Estimation of daily cortisol production and clearance rates in normal pubertal males by deconvolution analysis, J Clin Endocrinol Metab, 1993;76:1505–10.
6. Walker BR, Campbell JC, Fraser R, et al., Mineralocorticoid excess and inhibition of 11 beta-hydroxysteroid dehydrogenase in patients with ectopic ACTH syndrome, Clin Endocrinol (Oxf), 1992;37:483–92.
7. Stewart P, The adrenal cortex. In: Larsen P, Kronenberg H, Melmed S, Polonsky K (editors), Williams Textbook of Endocrinology, 10th ed, Philadelphia, USA: Saunders, 2003;491–551.
8. Torpy DJ, Ho JT, Corticosteroid-binding globulin gene polymorphisms: clinical implications and links to idiopathic chronic fatigue disorders, Clin Endocrinol (Oxf), 2007;67:161–7.
9. Breuner CW, Orchinik M, Plasma binding proteins as mediators of corticosteroid action in vertebrates, J Endocrinol, 2002;175:99–112.
10. Seckl JR, Walker BR, Minireview: 11beta-hydroxysteroid dehydrogenase type 1- a tissue-specific amplifier of glucocorticoid action, Endocrinology, 2001;142:1371–6.
11. Walker BR, Andrew R, Tissue production of cortisol by 11beta-hydroxysteroid dehydrogenase type 1 and metabolic disease, Ann N Y Acad Sci, 2006;1083:165–84.
12. Tomlinson JW, Walker EA, Bujalska IJ, et al., 11beta- hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response, Endocr Rev, 2004;25:831–66.
13. Dittmar KD, Demady DR, Stancato LF, et al., Folding of the glucocorticoid receptor by the heat shock protein (hsp) 90- based chaperone machinery. The role of p23 is to stabilize receptor.hsp90 heterocomplexes formed by hsp90.p60.hsp70, J Biol Chem, 1997;272:21213–20.
14. van der Laan S, Meijer OC, Pharmacology of glucocorticoids: beyond receptors, Eur J Pharmacol, 2008;585:483–91.
15. Freedman ND, Yamamoto KR, Importin 7 and importin alpha/importin beta are nuclear import receptors for the glucocorticoid receptor, Mol Biol Cell, 2004;15:2276–86.
16. Gross KL, Lu NZ, Cidlowski JA, Molecular mechanisms regulating glucocorticoid sensitivity and resistance, Mol Cell Endocrinol, 2009;300:7–16.
17. Meijsing SH, Pufall MA, So AY, et al., DNA binding site sequence directs glucocorticoid receptor structure and activity, Science, 2009;324:407–10.
18. Clark AR, Anti-inflammatory functions of glucocorticoid- induced genes, Mol Cell Endocrinol, 2007;275:79–97.
GCs are predominantly used as anti-inflammatory and immunosuppressive agents. Despite the undoubted clinical benefit obtained from the use of these drugs, the side-effect profile associated with their use remains a huge problem.43
immunosuppressive actions of these drugs predominantly feature GC-mediated transrepression, whereas the side effects often involve transactivation. Selective GR agonists with a pharmacological action mostly based on transrepression with little effect on activation could retain the desirable clinical effects of these drugs while considerably reducing side effects.43
Animal models demonstrating tissue-specific
knockout or overexpression of GC targets will also help provide a more accurate picture of GC action in vivo.
Antistress gene therapy is also a potential tool to protect against tissue impairment due to prolonged elevations in circulating GCs. Dumas and colleagues101
have recently demonstrated that tissue-specific expression
of 11-β-HSD-2 within the hippocampus offsets neurophysiological disruptions induced by chronically increased GC levels. Thus, a better understanding of tissue-specific GC physiology will allow us to develop more sensitive GC-based therapies and generate treatments aimed at improving outcomes in diseases/disorders associated with chronically increased GC levels. n
19. Bamberger CM, Schulte HM, Chrousos GP, Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids, Endocr Rev, 1996;17:245–61.
20. Bhavsar PK, Sukkar MB, Khorasani N, et al., Glucocorticoid suppression of CX3CL1 (fractalkine) by reduced gene promoter recruitment of NF-kappaB, FASEB J, 2008;22:1807–16.
21. Cato AC, Nestl A, Mink S, Rapid actions of steroid receptors in cellular signaling pathways, Sci STKE, 2002;2002:re9.
22. Hafezi-Moghadam A, Simoncini T, Yang Z, et al., Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase, Nat Med, 2002;8:473–9.
23. Solito E, Mulla A, Morris JF, et al., Dexamethasone induces rapid serine-phosphorylation and membrane translocation of annexin 1 in a human folliculostellate cell line via a novel nongenomic mechanism involving the glucocorticoid receptor, protein kinase C, phosphatidylinositol 3-kinase, and mitogen-activated protein kinase, Endocrinology, 2003;144:1164–74.
24. Taylor AD, Cowell AM, Flower J, Buckingham JC, Lipocortin 1 mediates an early inhibitory action of glucocorticoids on the secretion of ACTH by the rat anterior pituitary gland in vitro, Neuroendocrinology, 1993;58:430–39.
25. Song IH, Buttgereit F, Non-genomic glucocorticoid effects to provide the basis for new drug developments, Mol Cell Endocrinol, 2006;246:142–6.
26. Bartholome B, Spies CM, Gaber T, et al., Membrane glucocorticoid receptors (mGCR) are expressed in normal human peripheral blood mononuclear cells and up-regulated after in vitro stimulation and in patients with rheumatoid arthritis, FASEB J, 2004;18:70–80.
27. Montague CT, O’Rahilly S, The perils of portliness: causes and consequences of visceral adiposity, Diabetes, 2000;49:883–8.
28. Hautanen A, Raikkonen K, Adlercreutz H, Associations between pituitary-adrenocortical function and abdominal obesity, hyperinsulinaemia and dyslipidaemia in normotensive males, J Intern Med, 1997;241:451–61.
29. Kotelevtsev Y, Holmes MC, Burchell A, et al., 11beta- hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress, Proc Natl Acad Sci U S A, 1997;94:14924–9.
30. Masuzaki H, Paterson J, Shinyama H, et al., A transgenic model of visceral obesity and the metabolic syndrome, Science, 2001;294:2166–70.
31. Masuzaki H, Yamamoto H, Kenyon CJ, et al., Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice, J Clin Invest, 2003;112:83–90.
32. Paulmyer-Lacroix O, Boullu S, Oliver C, et al., Expression of the mRNA coding for 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue from obese patients: an in situ hybridization study, J Clin Endocrinol Metab, 2002;87:2701–5.
33. Rask E, Olsson T, Soderberg S, et al., Tissue-specific dysregulation of cortisol metabolism in human obesity, J Clin Endocrinol Metab, 2001;86:1418–21.
34. Stevens A, Ray DW, Zeggini E, et al., Glucocorticoid sensitivity
is determined by a specific glucocorticoid receptor haplotype, J Clin Endocrinol Metab, 2004;89:892–7.
35. van Rossum EF, Lamberts SW, Polymorphisms in the glucocorticoid receptor gene and their associations with metabolic parameters and body composition, Recent Prog Horm Res, 2004;59:333–57.
36. van Rossum EF, Roks PH, de Jong FH, et al., Characterization of a promoter polymorphism in the glucocorticoid receptor gene and its relationship to three other polymorphisms, Clin Endocrinol (Oxf), 2004;61:573–81.
37. Huizenga NA, Koper JW, De Lange P, et al., A polymorphism in the glucocorticoid receptor gene may be associated with and increased sensitivity to glucocorticoids in vivo, J Clin Endocrinol Metab, 1998;83:144–51.
38. Rosmond R, Chagnon YC, Holm G, et al., A glucocorticoid receptor gene marker is associated with abdominal obesity, leptin, and dysregulation of the hypothalamic-pituitary- adrenal axis, Obes Res, 2000;8:211–8.
39. van Rossum EF, Koper JW, van den Beld AW, et al., Identification of the BclI polymorphism in the glucocorticoid receptor gene: association with sensitivity to glucocorticoids in vivo and body mass index, Clin Endocrinol (Oxf), 2003;59:585–92.
40. Benediktsson R, Calder AA, Edwards CR, Seckl JR, Placental 11 beta-hydroxysteroid dehydrogenase: a key regulator of fetal glucocorticoid exposure, Clin Endocrinol (Oxf), 1997;46:161–6.
41. Edwards CR, Benediktsson R, Lindsay RS, Seckl JR, 11 beta- Hydroxysteroid dehydrogenases: key enzymes in determining tissue-specific glucocorticoid effects, Steroids, 1996;61:263–9.
42. Seckl JR, Chapman KE, Medical and physiological aspects of the 11beta-hydroxysteroid dehydrogenase system, Eur J Biochem, 1997;249:361–4.
43. Schacke H, Docke WD, Asadullah K, Mechanisms involved in the side effects of glucocorticoids, Pharmacol Ther, 2002;96:23–43.
44. Shibli-Rahhal A, Van Beek M, Schlechte JA, Cushing’s syndrome, Clin Dermatol, 2006;24:260–5.
45. Grundy SM, Metabolic syndrome: therapeutic considerations, Handb Exp Pharmacol, 2005;170:107–33.
46. Lambillotte C, Gilon P, Henquin JC, Direct glucocorticoid inhibition of insulin secretion. An in vitro study of dexamethasone effects in mouse islets, J Clin Invest, 1997;99:414–23.
47. Caperuto LC, Anhe GF, Amanso AM, et al., Distinct regulation of IRS proteins in adipose tissue from obese aged and dexamethasone-treated rats, Endocrine, 2006;29:391–8.
48. Corporeau C, Foll CL, Taouis M, et al., Adipose tissue compensates for defect of phosphatidylinositol 3’-kinase induced in liver and muscle by dietary fish oil in fed rats, Am J Physiol Endocrinol Metab, 2006;290:E78–E86.
49. Buren J, Liu HX, Jensen J, Eriksson JW, Dexamethasone impairs insulin signalling and glucose transport by depletion of insulin receptor substrate-1, phosphatidylinositol 3-kinase and protein kinase B in primary cultured rat adipocytes, Eur J Endocrinol, 2002;146:419–29.
50. Whorwood CB, Donovan SJ, Flanagan D, et al., Increased glucocorticoid receptor expression in human skeletal muscle cells may contribute to the pathogenesis of the metabolic syndrome, Diabetes, 2002;51:1066–75.
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