11β-Hydroxysteroid dehydrogenase type 1 and bone

Summary

Intracellular enzymatic metabolism of glucocorticoids is an important contributor to glucocorticoid action. The most extensively studied glucocorticoid metabolising enzymes are the 11β-hydroxysteroid dehydrogenases (11β-HSDs). These enzymes interconvert hormonally inactive glucocorticoids such as cortisone and dehydrocorticosterone with their active counterparts cortisol and corticosterone. 11β-HSDs have been reported to be expressed in bone and bone cells. This article reviews the literature relating to the expression, activity and functional consequences of 11β-HSD expression in bone. This activity appears to have clinical consequences in terms of predisposition towards osteoporosis and fracture and in the variation between individuals in the sensitivity of bone to therapeutic glucocorticoids. The existence of this enzyme system within bone opens up opportunities for new treatments to protect bone from the adverse effects of glucocorticoids.

Zusammenfassung

Der intrazelluläre enzymatische Metabolismus der Glukokortikoide trägt entscheidend zur Glukokortikoidwirkung bei. Die am meisten untersuchten Enzyme des Glukokortikoid-metabolismus sind die 11β-Hydroxysteroid Dehydrogenasen (11β-HSDs). Diese Enzyme können hormonell inaktive Metaboliten wie Kortison und Dehydrokortikosteron in ihre aktiven Metaboliten Kortisol und Kortikosteron umwandeln. 11β-HSDs werden im Knochen und in Knochenzellen exprimiert. Dieser Artikel gibt einen Überblick über die Literatur hinsichtlich der Expression, Aktivität und den funktionellen Folgen der 11β-HSD-Expression im Knochen. Die Enzymaktivität scheint für eine Osteoporose und Frakturen zu prädisponieren. Weiterhin scheint die Empfindlichkeit von Individuen bezüglich einer Glukokortikoidtherapie davon beeinflusst zu sein. Die Anwesenheit dieses Enzymsystems im Knochen eröffnet auch Chancen für neue Therapiemöglichkeiten, um den Knochen vor negativen Effekten der Glukokortikoide zu schützen.

Keywords

Bone - osteoblasts - cortisol - 11beta-hydroxysteroid dehydrogenase

Schlüsselwörter

Knochen - Osteoblasten - Kortisol - 11β-Hydroxysteroid-Dehydrogenase

• References

• 1 Raza K, Hardy R, Cooper MS. The 11beta-hydroxysteroid dehydrogenase enzymes – arbiters of the effects of glucocorticoids in synovium and bone. Rheumatology (Oxford) 2010; 49 (11) 2016-2023.
• 2 Gathercole LL, Lavery GG, Morgan SA. et al. 11beta-hydroxysteroid dehydrogenase 1: translational and therapeutic aspects. Endocr Rev 2013; 34 (04) 525-555.
• 3 Chapman K, Holmes M, Seckl J. 11beta-hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action. Physiological reviews 2013; 93 (03) 1139-1206.
• 4 Bellows CG, Ciaccia A, Heersche JN. Osteoprogenitor cells in cell populations derived from mouse and rat calvaria differ in their response to corticosterone, cortisol, and cortisone. Bone 1998; 23 (02) 119-125.
• 5 Bland R, Worker CA, Noble BS. et al. Characterization of 11b-hydroxysteroid dehydrogenase activity and corticosteroid receptor expression in human osteosarcoma cell lines. J Endocrinol 1999; 161 (03) 455-464.
• 6 Rabbitt E, Lavery GG, Walker EA. et al. Pre-receptor regulation of glucocorticoid action by 11b-hydroxysteroid dehydrogenase: a novel determinant of cell proliferation. FASEB J 2002; 16: 36-44.
• 7 Patel P, Hardy R, Sumathi V. et al. Expression of 11beta-hydroxysteroid dehydrogenase enzymes in human osteosarcoma: potential role in pathogenesis and as targets for treatments. Endocr Relat Cancer 2012; 19 (04) 589-598.
• 8 Cooper MS, Bujalska I, Rabbitt E. et al. Modulation of 11b-hydroxysteroid dehydrogenase isozymes by proinflammatory cytokines in osteoblasts: an autocrine switch from glucocorticoid inactivation to activation. J Bone Miner Res 2001; 16 (06) 1037-1044.
• 9 Cooper MS, Rabbitt EH, Goddard PE. et al. Osteoblastic 11b-hydroxysteroid dehydrogenase type 1 activity increases with age and glucocorticoid exposure. J Bone Miner Res 2002; 17 (06) 979-986.
• 10 Kaur K, Hardy R, Ahasan MM. et al. Synergistic induction of local glucocorticoid generation by inflammatory cytokines and glucocorticoids: implications for inflammation associated bone loss. Ann Rheum Dis 2010; 69 (06) 1185-1190.
• 11 Condon J, Gosden C, Gardener D. et al. Expression of type 2 11b-hydroxysteroid dehydrogenase and corticosteroid hormone receptors in early human fetal life. J Clin Endocrinol Metab 1998; 83 (12) 4490-4497.
• 12 Cooper MS, Walker EA, Bland R. et al. Expression and functional consequences of 11b-hydroxysteroid dehydrogenase activity in human bone. Bone 2000; 27 (03) 375-381.
• 13 Eijken M, Hewison M, Cooper MS. et al. 11b-Hydroxysteroid dehydrogenase expression and glucocorticoid synthesis are directed by a molecular switch during osteoblast differentiation. Mol Endocrinol 2005; 19 (03) 621-631.
• 14 Ahasan MM, Hardy R, Jones C. et al. Inflammatory regulation of glucocorticoid metabolism in mesenchymal stromal cells. Arthritis Rheum 2012; 64 (07) 2404-2413.
• 15 Weinstein RS, Wan C, Liu Q. et al. Endogenous glucocorticoids decrease skeletal angiogenesis, vascularity, hydration, and strength in aged mice. Aging Cell 2010; 09: 147-161.
• 16 Justesen J, Mosekilde L, Holmes M. et al. Mice Deficient in 11b-Hydroxysteroid dehydrogenase Type 1 Lack Bone Marrow Adipocytes but Maintain Normal Bone Formation. Endocrinology 2004; 145 (04) 1916-1925.
• 17 Kotelevtsev Y, Holmes MC, Burchell A. et al. 11b-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress. Proc Natl Acad Sci USA 1997; 94 (26) 14924-14929.
• 18 Tiganescu A, Tahrani AA, Morgan SA. et al. 11beta-Hydroxysteroid dehydrogenase blockade prevents age-induced skin structure and function defects. J Clin Invest 2013; 123 (07) 3051-3060.
• 19 Shi L, Sanchez-Guijo A, Hartmann MF. et al. Higher glucocorticoid secretion in the physiological range is associated with lower bone strength at the proximal radius in healthy children: importance of protein intake adjustment. Journal of bone and mineral research 2015; 30 (02) 240-248.
• 20 Hwang JY, Lee SH, Kim GS. et al. HSD11B1 polymorphisms predicted bone mineral density and fracture risk in postmenopausal women without a clinically apparent hypercortisolemia. Bone 2009; 45 (06) 1098-1103.
• 21 Feldman K, Szappanos A, Butz H. et al. The rs4844880 polymorphism in the promoter region of the HSD11B1 gene associates with bone mineral density in healthy and postmenopausal osteoporotic women. Steroids 2012; 77 (13) 1345-1351.
• 22 Siggelkow H, Etmanski M, Bozkurt S. et al. Genetic polymorphisms in 11beta-hydroxysteroid dehydrogenase type 1 correlate with the postdexamethasone cortisol levels and bone mineral density in patients evaluated for osteoporosis. The Journal of clinical endocrinology and metabolism 2014; 99 (02) E293-E302.
• 23 Szappanos A, Patocs A, Gergics P. et al. The 83,557insA variant of the gene coding 11beta-hydroxysteroid dehydrogenase type 1 enzyme associates with serum osteocalcin in patients with endogenous Cushing’s syndrome. The Journal of steroid biochemistry and molecular biology 2011; 123 (1–2): 79-84.
• 24 Hardy R, Cooper MS. Adrenal gland and bone. Arch Biochem Biophys 2010; 503 (01) 137-145.
• 25 Cooper MS, Syddall HE, Fall CH. et al. Circulating cortisone levels are associated with biochemical markers of bone formation and lumbar spine BMD: the Hertfordshire Cohort Study. Clin Endocrinol (Oxf) 2005; 62 (06) 692-697.
• 26 Arampatzis S, Pasch A, Lippuner K, Mohaupt M. Primary male osteoporosis is associated with enhanced glucocorticoid availability. Rheumatology 2013; 52 (11) 1983-1991.
• 27 Hardy R, Cooper MS. Bone loss in inflammatory disorders. J Endocrinol 2009; 201 (03) 309-320.
• 28 Schmidt M, Weidler C, Naumann H. et al. Reduced capacity for the reactivation of glucocorticoids in rheumatoid arthritis synovial cells: possible role of the sympathetic nervous system?. Arthritis Rheum 2005; 52 (06) 1711-1720.
• 29 Hardy R, Rabbitt EH, Filer A. et al. Local and systemic glucocorticoid metabolism in inflammatory arthritis. Ann Rheum Dis 2008; 67 (09) 1204-1210.
• 30 Diarra D, Stolina M, Polzer K. et al. Dickkopf-1 is a master regulator of joint remodeling. Nature Medicine 2007; 13 (02) 156-163.
• 31 Hardy R, Juarez M, Naylor A. et al. Synovial DKK1 expression is regulated by local glucocorticoid metabolism in inflammatory arthritis. Arthritis Res Ther 2012; 14 (05) R226.
• 32 Chapman KE, Coutinho AE, Gray M. et al. The role and regulation of 11beta-hydroxysteroid dehydrogenase type 1 in the inflammatory response. Mol Cell Endocrinol 2009; 301 (1–2): 123-131.
• 33 Coutinho AE, Gray M, Brownstein DG. et al. 11b-HSD type 1, but not type 2, deficiency worsens acute inflammation and experimental arthritis in mice. Endocrinology 2012; 153 (01) 234-240.
• 34 Ergang P, Leden P, Vagnerova K. et al. Local metabolism of glucocorticoids and its role in rat adjuvant arthritis. Molecular and cellular endocrinology 2010; 323 (02) 155-160.
• 35 Diederich S, Eigendorff E, Burkhardt P. et al. 11b-hydroxysteroid dehydrogenase types 1 and 2: an important pharmacokinetic determinant for the activity of synthetic mine. J Clin Endocrinol-Metab 2002; 87 (12) 5695-5701.
• 36 Cooper MS, Blumsohn A, Goddard PE. et al. 11b-hydroxysteroid dehydrogenase type 1 activity predicts the effects of glucocorticoids on bone. J Clin Endocrinol Metab 2003; 88 (08) 3874-3877.
• 37 Cooper MS, Kriel H, Sayers A. et al. Can 11beta-hydroxysteroid dehydrogenase activity predict the sensitivity of bone to therapeutic glucocorticoids in inflammatory bowel disease?. Calcified tissue international 2011; 89 (03) 246-251.
• 38 Hardy RS, Filer A, Cooper MS. et al. Differential expression, function and response to inflammatory stimuli of 11b-hydroxysteroid dehydrogenase type 1 in human fibroblasts: a mechanism for tissue-specific regulation of inflammation. Arthritis Res Ther 2006; 08 (04) R108.
• 39 Hermanowski-Vosatka A, Gerhold D, Mundt SS. et al. PPARalpha agonists reduce 11beta-hydroxysteroid dehydrogenase type 1 in the liver. Biochem Biophys Res Commun 2000; 279 (02) 330-336.
• 40 Walker BR, Connacher AA, Lindsay RM. et al. Carbenoxolone increases hepatic insulin sensitivity in man: a novel role for 11-oxosteroid reductase in enhancing glucocorticoid receptor activation. J Clin Endocrinol Metab 1995; 80 (11) 3155-3159.
• 41 Shah S, Hermanowski-Vosatka A, Gibson K. et al. Efficacy and safety of the selective 11beta-HSD-1 inhibitors MK-0736 and MK-0916 in overweight and obese patients with hypertension. J Am Soc Hypertens 2011; 05 (03) 166-176.
• 42 Feig PU, Shah S, Hermanowski-Vosatka A. et al. Effects of an 11beta-hydroxysteroid dehydrogenase type 1 inhibitor, MK-0916, in patients with type 2 diabetes mellitus and metabolic syndrome. Diabetes Obes Metab 2011; 13 (06) 498-504.
• 43 Rosenstock J, Banarer S, Fonseca VA. et al. The 11-beta-hydroxysteroid dehydrogenase type 1 inhibitor INCB13739 improves hyperglycemia in patients with type 2 diabetes inadequately controlled by metformin monotherapy. Diabetes Care 2010; 33 (07) 1516-1522.
• 44 Nixon M, Wake DJ, Livingstone DE. et al. Salicylate downregulates 11beta-HSD1 expression in adipose tissue in obese mice and in humans, mediating insulin sensitization. Diabetes 2012; 61 (04) 790-796.