Adrenal Steroid Laboratory Projects
 

1. The role of local steroid production in post-menopausal osteoporosis

Although it has been known for many decades that high levels of cortisol (anti-inflammatory steroids) can cause bone loss, Prof Cooper was first to demonstrate that high local production of cortisol within bone tissue could account for age-related bone loss. These studies have led to a phase II clinical trial studying the effectiveness of a chemical inhibitor of the steroid producing enzyme in post-menopausal women with low bone density.

Dr Jinwen Tu
Prof Mark Cooper

References:
Tiganescu A, Tahrani AA, Morgan SA, Otranto M, Desmoulière A, Abrahams L, Hassan-Smith Z, Walker EA, Rabbitt EH, Cooper MS, Amrein K, Lavery GG, Stewart PM. 11-Hydroxysteroid dehydrogenase blockade prevents age-induced skin structure and function defects. J Clin Invest. 2013 Jul 1;123(7):3051-60.
Hardy R, Cooper MS. Glucocorticoid-induced osteoporosis – a disorder of mesenchymal stromal cells? Frontiers in Endocrinology 2011 2:24
Cooper MS, Walker EA, Bland R, Fraser WD, Hewison M, Stewart PM. Expression and functional consequences of 11-hydroxysteroid dehydrogenase activity in human bone. Bone 2000; 27:375-81

2. The role of local steroid production in the development and persistence of rheumatoid arthritis

Anti-inflammatory steroids have been used since the 1950s as treatments for rheumatoid arthritis (RA). Defects in the body’s own production of steroids have also been implicated in the development or persistence of RA but the exact nature of these abnormalities has been difficult to define. In association with rheumatology colleagues at the University of Birmingham we have shown that active steroids are generated in large amounts within the inflamed joint. Although this local production can reduce the amount of inflammation within the joint it is unclear if this is a help or a hindrance in the resolution of inflammatory arthritis. This is an important question to answer since it might allow us to develop ways of switching off arthritis before it becomes persistent.

Dr Jinwen Tu
Prof Mark Cooper

References:
Nanus DE, Filer AD, Hughes B, Fisher BA, Taylor PC, Stewart PM, Buckley CD, McInnes I, Cooper MS, Raza K. TNFα regulates cortisol metabolism in vivo in patients with inflammatory arthritis. Ann Rheum Dis. 2014 Jan 2. [Epub ahead of print]
Kaur K, Hardy R, Ahasan MM, Eijken M, van Leeuwen JP, Filer A, Thomas AM, Raza K, Buckley CD, Stewart PM, Rabbitt EH, Hewison M, Cooper MS. Synergistic induction of local glucocorticoid generation by inflammatory cytokines and glucocorticoids: implications for inflammation associated bone loss. Annals of the Rheumatic Diseases. 2010 69:1185-90
Hardy RS, Rabbitt EH, Filer A, Emery P, Hewison M, Stewart PM, Gittoes N, Buckley CD, Raza K, Cooper MS. Local and systemic glucocorticoid metabolism in inflammatory arthritis. Annals of the Rheumatic Diseases. 2008 67:1204-10

3. The role of local steroid production in bone and cartilage damage during joint inflammation

Bone loss is very common in people with joint disease and contributes significantly to long-term disability. We have shown that osteoblasts make anti-inflammatory steroids during inflammation and that this production is likely to be a major factor in inflammation-associated bone loss. Cartilage is the joint lining tissue and is made by a specialised type of cell called the chondrocyte. These cells are very sensitive to the effects of glucocorticoids. We have previously shown that cells that are closely related to chondrocytes and chondrocytes themselves have the capacity to generate glucocorticoids. In association with Hong Zhou and Markus Seibel at the ANZAC Research Institute we are exploring whether this regulation is important in normal cartilage function and the response of cartilage to joint inflammation.

Dr Jinwen Tu
Prof Mark Cooper

References:
Hardy R, Juarez M, Naylor A, Tu J, Rabbitt EH, Filer A, Stewart PM, Buckley CD, Raza K, Cooper MS. Synovial DKK1 expression is regulated by local glucocorticoid metabolism in inflammatory arthritis. Arthritis Research and Therapy 2012 Oct 18; 14:R226
de Pablo P, Cooper MS, Buckley CD. Association between bone mineral density and C-reactive protein in a large population-based sample. Arthritis and Rheumatism 2012 64(8):2624-31
Kaur K, Hardy R, Ahasan MM, Eijken M, van Leeuwen JP, Filer A, Thomas AM, Raza K, Buckley CD, Stewart PM, Rabbitt EH, Hewison M, Cooper MS. Synergistic induction of local glucocorticoid generation by inflammatory cytokines and glucocorticoids: implications for inflammation associated bone loss. Annals of the Rheumatic Diseases 2010 69:1185-90

4. The endocrinology of critical illness

During severe illness there are many changes in the level of adrenal steroids and other hormones. These changes appear to be important in the body’s ability to survive the severe stress of major illness. In collaboration with the University of Birmingham we are currently examining aspects of the body’s response to critical illness and the implications that this has in severe sepsis and acute lung injury.

Prof Mark Cooper

References:
Cooper MS, Thickett DR, Stewart PM. Reduced cortisol metabolism during critical illness. N Engl J Med. 2013 Aug 1;369(5):480.
Parek D, Dancer RC, Lax S, Cooper MS, Martineau AR, Fraser WD, Tucker O, Alderson D, Perkins GD, Gao-Smith F, Thickett DR. Vitamin D to prevent acute lung injury following oesophagectomy (VINDALOO): study protocol for a randomised placebo controlled trial. Trials 2013 14:100
Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. New England Journal of Medicine 2003; 348:727-34

5. The role of glucocorticoid metabolism in osteosarcoma

Osteosarcoma is the commonest primary bone cancer in children and adolescents. We have demonstrated that these tumour cells can break down anti-inflammatory adrenal steroids and thus become resistant to their effects. We are currently determining the clinical importance of this effect and whether preventing this break down of steroids might lead to better outcomes in osteosarcoma.

Dr Jinwen Tu
Prof Mark Cooper

References:
Patel P, Hardy R, Sumathi V, Bartle G, Kindblom LG, Grimer R, Bujalska I, Stewart PM, Rabbitt E, Gittoes N, Cooper MS. Expression of 11-Hydroxysteroid dehydrogenase enzymes in human osteosarcoma: Potential role in pathogenesis and as targets for treatments. Endocrine-Related Cancer 2012 19:589-98
Rabbitt EH, Lavery GG, Walker EA, Cooper MS, Stewart PM, Hewison M. Pre-receptor regulation of glucocorticoid action by 11-hydroxysteroid dehydrogenase: a novel determinant of cell proliferation. FASEB Journal 2002; 16:36-44