|Professor of Musculoskeletal Biology||
I dot Clark at uea dot ac dot uk
Tel: +44 (0)1603 59 2760
|Bio-Medical Research Centre (BMRC) 02.01b|
2006 – date: Professor of Musculoskeletal Biology, School of Biological Sciences, University of East Anglia, Norwich, UK
2001 - 2006: Reader, School of Biological Sciences, University of East Anglia, Norwich, UK
2001: Team Leader, AstraZeneca Pharmaceuticals, Alderley Park, Cheshire, UK (sabbatical)
1996 - 2000: Arthritis Research Campaign Postdoctoral Research Fellow, School of Biological Sciences, University of East Anglia, Norwich, UK.
1994 - 1996: Arthritis Research Campaign Postdoctoral Research Fellow, Rheumatology Research Unit, Addenbrooke's Hospital, Cambridge, UK.
1993: Arthritis and Rheumatism Council Copeman Fellow. Taken up in the laboratory of Professor C.E. Brinckerhoff, Dept. of Biochemistry and Medicine, Dartmouth Medical School, New Hampshire USA.
1990 - 1992: Postdoctoral Fellow (funded by SmithKline Beecham Pharmaceuticals), Rheumatology Research Unit, Addenbrooke's Hospital, Cambridge, UK.
Osteoarthritis is a degenerative joint disease for which there are no disease-modifying drugs. It is a leading cause of disability in the UK. Approximately 8.5 million people in the UK have moderate to severe osteoarthritis and a recent survey shows that around 70% of them are in constant pain. Increasing age and obesity are both major risk factors for osteoarthritis and the health and economic burden of this disease will increase in the future. The Clark laboratory is investigating (i) the role of microRNAs in cartilage homeostasis and (ii) the impact of dietary bioactives on joint health.
(i) MicroRNAs (miRNAs) are small non-coding RNAs that have recently been recognised as important regulators of gene expression in human cells. A number of miRNAs are regulated across chondrocyte differentiation and their function is beginning to be delineated. Similarly miRNAs are differentially expressed in osteoarthritic cartilage compared to normal tissue. MicroRNA-140, highly and selectively expressed in cartilage, has been the focus of much work to date, though the full gamut of its actions is still to be defined. We are investigating miR-455 and miR-29, as well as a number of novel microRNAs that we have found in osteoarthritic chondrocytes.
(ii) A number of plant-derived phytochemicals have been proposed to have positive benefit on joint health and osteoarthritis though predominantly, these have not been studied in man to date. There are some published population-based study data to suggest that dietary constituents are associated with a reduction in the progression of OA in man. However, to date, dietary intervention trials have been small and of varying design, resulting in difficulty in interpreting the available data. We are investigating the role of sulforaphane, an isothiocyanate derived from eating broccoli and related vegetables, in osteoarthritis. So far, this compound has shown efficacy in three laboratory models of disease. We are currently undertaking a proof-of-principle human trial to ascertain if it will be similarly effective in man. We are also screening a number of diet-derived compounds for similar activity in chondrocytes with a view to investigating synergy between them.
Dupuytren’s disease (DD) is a common disabling condition leading to contracture of the fingers, affecting over 2 million people in the UK. The only current treatment for established DD is surgery with high recurrence rates. Further surgery becomes more invasive with higher complication rates and incomplete contracture correction. There are no known drug treatments for the condition at present.
In the late 1980s and early 1990s, inhibitors of the matrix metalloproteinase family were developed for the treatment of cancers. Some of these compounds gave the side effect of a Dupuytren’s-like contracture. We have been trying to understand the role of metalloproteinases in Dupuytren’s disease. We measured the expression of two main families of metalloproteinases (the MMPs and the ADAMTSs) in tissue taken from Dupuytren’s patients at surgery. Furthermore, we were able to show a correlation between the levels of specific proteinases and recurrence of contracture post-surgery. We have gone on to show roles for specific proteases in models of cell-mediated contraction.
My teaching interests are around molecular biology and gene expression, cartilage biology, proteinases and osteoarthritis.
My teaching interests are around molecular biology and gene expression, cartilage biology, proteinases and osteoarthritis.
Soond, Surinder M., Smith, Paul G., Wahl, Lloyd, Swingler, Tracey E., Clark, Ian M., Hemmings, Andrew M. and Chantry, Andrew (2013) Novel WWP2 ubiquitin ligase isoforms as potential prognostic markers and molecular targets in cancer. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1832 (12). pp. 2127-2135. ISSN 09254439
Davidson, Rose K, Jupp, Orla, De Ferrars, Rachel, Kay, Colin D, Culley, Kirsty L, Norton, Rosemary, Driscoll, Clare, Vincent, Tonia L, Donell, Simon T, Bao, Yongping and Clark, Ian M (2013) Sulforaphane represses matrix-degrading proteases and protects cartilage from destruction in vitro and in vivo : Sulforaphane is Protective in the Articular Joint. Arthritis & Rheumatism. n/a-n/a. ISSN 00043591 (In Press)
Le, Linh T. T., Swingler, Tracey E. and Clark, Ian M. (2013) Review: The Role of MicroRNAs in Osteoarthritis and Chondrogenesis : MicroRNAS in OA. Arthritis & Rheumatism, 65 (8). pp. 1963-1974. ISSN 00043591
Culley, Kirsty L., Hui, Wang, Barter, Matt J., Davidson, Rose K., Swingler, Tracey E., Destrument, Auriane P. M., Scott, Jenny L., Donell, Simon T., Fenwick, Steve, Rowan, Andrew D., Young, David A. and Clark, Ian M. (2013) Class I Histone Deacetylase Inhibition Modulates Metalloproteinase Expression and Blocks Cytokine-Induced Cartilage Degradation : Class I HDAC Inhibition is Chondroprotective. Arthritis & Rheumatism, 65 (7). pp. 1822-1830. ISSN 00043591
Radwan, Marta, Gavriilidis, Christos, Robinson, John H., Davidson, Rosemary, Clark, Ian M., Rowan, Andrew D. and Young, David A. (2013) Matrix Metalloproteinase 13 Expression in Response to Double-Stranded RNA in Human Chondrocytes. Arthritis & Rheumatism, 65 (5). pp. 1290-1301. ISSN 00043591
Wilkinson, JM, Davidson, RK, Swingler, TE, Jones, ER, Corps, AN, Johnston, P, Riley, GP, Chojnowski, AJ and Clark, IM (2012) MMP-14 and MMP-2 are key metalloproteases in Dupuytren's disease fibroblast-mediated contraction. BBA - Biochimica et Biophysica Acta, 1822 (6). pp. 897-905.
Ollivere, B, Wimhurst, JA, Clark, IM and Donell, SM (2012) Current concepts in osteolysis. Journal of Bone and Joint Surgery - British Volume, 94-B (1). pp. 10-15. ISSN 0301-620X
Swingler, TE, Wheeler, G, Carmont, V, Elliott, HR, Barter, MJ, Abu-Elmagd, M, Donell, ST, Boot-Handford, RP, Hajihosseini, MK, Munsterberg, A, Dalmay, T, Young, DA and Clark, IM (2012) The expression and function of microRNAs in chondrogenesis and osteoarthritis. Arthritis & Rheumatism, 64 (6). pp. 1909-1919.
Fields, J, Gardner-Mercer, J, Borgmann, K, Clark, IM and Ghorpade, A (2011) CCAAT/enhancer binding protein β expression is increased in the brain during HIV-1-infection and contributes to regulation of astrocyte tissue inhibitor of metalloproteinase-1. Journal of Neurochemistry, 118. pp. 93-104.
Milner, JM, Patel, A, Davidson, RK, Swingler, TE, Desilets, A, Young, DA, Kelso, EB, Donell, ST, Cawston, TE, Clark, IM, Ferrell, WR, Plevin, R, Lockhart, JC, Leduc, R and Rowan, AD (2010) Matriptase is a novel initiator of cartilage matrix degradation in osteoarthritis. Arthritis and rheumatism, 62 (7). pp. 1955-1966. ISSN 1529-0131
Milner, JM, Patel, A, Davidson, RK, Swingler, TE, Desilets, A, Young, DA, Kelso, EB, Donell, ST, Cawston, TE, Clark, IM, Ferrell, WR, Plevin, R, Lockhart, JC, Leduc, R and Rowan, AD (2010) Matriptase is a novel initiator of cartilage matrix degradation in osteoarthritis. Arthritis & Rheumatism, 62 (4). pp. 1955-1966.
Scott, JL, Gabrielides, C, Davidson, RK, Swingler, TE, Clark, IM, Wallis, GA, Boot-Handford, RP, Kirkwood, TBL, Talyor, RW and Young, DA. (2010) Superoxide dismutase downregulation in osteoarthritis progression and end-stage disease. Annals of the Rheumatic Diseases, 69 (8). pp. 1502-1510. ISSN 0003-4967
Pais, H, Nicolas, FE, Soond, S, Swingler, T, Clark, I, Chantry, A, Moulton, V and Dalmay, T (2010) Analyzing mRNA expression identifies Smad3 as a microRNA-140 target regulated only at protein level. RNA, 16 (3). pp. 489-494. ISSN 1355-8382
Barter, MJ, Pybus, L, Litherland, GJ, Rowan, AD, Clark, IM, Edwards, DR, Cawston, TE and Young, DA (2010) HDAC-mediated control of ERK- and PI3K-dependent TGF-β-induced extracellular matrix-regulating genes. Matrix Biology, 29 (7). pp. 602-612.
Swingler, TE, Kevorkian, L, Culley, KL, Illman, SA, Young, DA, Parker, AE, Lohi, J and Clark, IM (2010) MMP28gene expression is regulated by Sp1 transcription factor acetylation. Biochemical Journal, 427 (3). pp. 391-400. ISSN 0264-6021
Williams, FMK, Skinner, J, Spector, TD, Cassidy, A, Clark, IM, Davidson, RM and Macgregor, AJ (2010) Dietary garlic and hip osteoarthritis: evidence of a protective effect and putative mechanism of action. BMC Musculoskeletal Disorders, 11 (1). p. 280. ISSN 1471-2474
Rodgers, U.R., Kevorkian, L., Surridge, A.K., Waters, J.G., Swingler, T.E., Culley, K., Illman, S., Lohi, J., Parker, A.E. and Clark, I.M. (2009) Expression and function of matrix metalloproteinase (MMP)-28. Matrix Biology, 28. pp. 263-272.
Surridge, A.K., Rodgers, U.R., Swingler, T.E., Davidson, R.K., Kevorkian, L., Norton, R., Waters, J.G., Goldring, M.B., Parker, A.E. and Clark, I.M. (2009) Characterization and regulation of ADAMTS-16. Matrix Biology, 28. pp. 416-424.
Swingler, T.E., Waters, J.G., Davidson, R.K., Pennington, C.J., Puente, X.S., Darrah, C., Cooper, A., Donell, S.T., Guile, G.R., Wang, W. and Clark, I.M. (2009) Degradome expression profiling in human articular cartilage. Arthritis Research & Therapy, 11. p. 96.
Clark, IM, Swingler, TE, Sampieri Ramirez, CL and Edwards, DR (2008) The regulation of matrix metalloproteinases and their inhibitors. The International Journal of Biochemistry & Cell Biology, 40 (6-7). pp. 1362-1378.
Clark, I, Macgregor, A and Donell, ST (2008) The genetic association between asporin and osteoarthritis. The Knee, 15 (3). vii-viii.
Johnston, P., Larson, D., Clark, I.M. and Chojnowski, A.J. (2008) Metalloproteinase gene expression correlates with clinical outcome in Dupuytren's disease. Journal of Hand Surgery - American Volume, 33. pp. 1160-1167.
Sampieri, C.L., Nuttall, R.K., Young, D.A., Goldspink, D., Clark, I.M. and Edwards, D.R. (2008) Activation of p38 and JNK MAPK pathways abrogates requirement for new protein synthesis for phorbol ester mediated induction of select MMP and TIMP genes. Matrix Biology, 27. pp. 128-138.
Zhang, Q., Hu, Wi, Litherland, G.J., Barter, M.J., Davidson, Rosemary, Darrah, C., Donell, ST, Clark, I.M., Cawston, T.E., Robinson, J.H., Rowan, A.D. and Young, D.A. (2008) Differential Toll-like receptor-dependent collagenase expression in chondrocytes. Annals of the Rheumatic Diseases, 67. pp. 1633-1641.
Johnston, P, Chojnowski, A, Davidson, R, Riley, Graham, Donell, S and Clark, I (2007) A Complete Expression Profile of Matrix-Degrading Metalloproteinases in Dupuytren’s Disease. The Journal of Hand Surgery, 32 (3). pp. 343-351.
Clark, I.M., Swingler, T.E. and Young, D.A. (2007) Acetylation in the regulation of MMP and TIMP gene expression. Frontiers in Bioscience, 12. pp. 528-535.
Jones, GC, Corps, AN, Pennington, CJ, Clark, IM, Edwards, DR, Bradley, MM, Hazleman, BL and Riley, GP (2006) Expression profiling of metalloproteinases and tissue inhibitors of metalloproteinases in normal and degenerate human achilles tendon. Arthritis & Rheumatism, 54 (3). pp. 832-842. ISSN 0004-3591
Davidson, R.K., Waters, J.G., Kevorkian, L., Darrah, C., Cooper, A., Donell, S.T. and Clark, I.M. (2006) Expression profiling of metalloproteinases and their inhibitors in synovium and cartilage. Arthritis Research and Therapy, 8 (4). p. 124.
Engers, R., Springer, E., Kehren, V., Simic, T., Young, D.A., Beier, J., Klotz, L.O., Clark, I.M., Sies, H. and Gabbert, H.E. (2006) Rac upregulates tissue inhibitor of metalloproteinase-1 expression by redox-dependent activation of extracellular signal-regulated kinase signalling. FEBS Journal, 273. pp. 4754-4769.
Milner, J.M., Kevorkian, L., Young, D.A., Jones, D., Wait, R., Donell, ST, Barksby, E., Patterson, A.M., Middleton, J., Cravatt, B.F., Clark, I.M., Rowan, A.D. and Cawston, T.E. (2006) Fibroblast activation protein alpha is expressed by chondrocytes following a pro-inflammatory stimulus and is elevated in osteoarthritis. Arthritis Research & Therapy, 8 (1). pp. 1186-1877.
Tuddenham, Lee, Wheeler, G., Ntouniafousara, S., Waters, J., Hajihosseini, Mohammad, Clark, Ian and Dalmay, Tamas (2006) The cartilage specific microRNA-140 targets histone deacetylase 4 in mouse cells. FEBS Letters, 580 (17). pp. 4214-4217.
Porter, S., Clark, I.M., Kevorkian, L. and Edwards, D.R. (2005) The ADAMTS metalloproteinases. Biochemical Journal, 386. pp. 15-27.
Young, D.A., Billingham, O., Sampieri, C.L., Edwards, D.R. and Clark, I.M. (2005) Differential effects of histone deacetylase inhibitors on phorbol ester- and TGF-beta 1 induced murine tissue inhibitor of metalloproteinases-1 gene expression. FEBS Journal, 272. pp. 1912-1926.
Young, D.A., Lakey, R.L., Pennington, C.J., Jones, D., Kevorkian, L., Edwards, D.R., Cawston, T.E. and Clark, I.M. (2005) Histone deacetylase inhibitors modulate metalloproteinase gene expression in chondrocytes and block cartilage resorption. Arthritis Research & Therapy, 7 (3). pp. 503-512. ISSN 1478-6354
Kevorkian, Lara, Young, D.A., Darrah, C., Donell, ST, Shepstone, Lee, Porter, S., Brockbank, S.M.V., Edwards, D.R., Parker, A.E. and Clark, I.M. (2004) Expression profiling of metalloproteinases and their inhibitors in cartilage. Arthritis and rheumatism, 50 (1). pp. 131-141. ISSN 0004-3591
Young, D.A., Gavrilov, S., Pennington, C.J., Nuttall, R.K., Edwards, D.R., Kitsis, R.N. and Clark, I.M. (2004) Expression of metalloproteinases and inhibitors in the differentiation of P19CL6 cells into cardiac myocytes. Biochemical and Biophysical Research Communications, 322. pp. 759-765.
Hall, MC, Young, DA, Waters, JG, Rowan, AD, Chantry, A, Edwards, DR and Clark, IM (2003) The comparative role of activator protein 1 and Smad factors in the regulation of Timp-1 and MMP-1 gene expression by transforming growth factor-beta 1. Journal of Biological Chemistry, 278 (12). pp. 10304-10313.
Clark, I.M. and Parker, A.E. (2003) Metalloproteinases: their role in arthritis and potential as therapeutic targets. Expert Opinion in Therapeutic Targets, 7. pp. 19-34.
Hall, M.C., Young, D.A., Rowan, A.D., Edwards, D.R. and Clark, I.M. (2002) Cryptic promoter activity of pBLCAT3 induced by overexpression of AP1 factors. Biotechniques, 33. pp. 1004-1008.
Koshy, P.J.T., Lundy, C.J., Rowan, A.D., Porter, S., Edwards, D.R., Hogan, A., Clark, I.M. and Cawston, T.E. (2002) The modulation of matrix metalloproteinase (MMP) and A Disintegrin And Metalloproteinase (ADAM) gene expression in human chondrocytes by interleukin-1 and oncostatin M. Arthritis and rheumatism, 46. pp. 961-967.
Murphy, G., Knauper, K., Atkinson, S., Butler, G., English, W., Hutton, M., Stracke, J. and Clark, Ian (2002) Matrix metalloproteinases in arthritic disease. Arthritis Research and Therapy, 4. pp. 539-549.
Price, J.S., Waters, J.G., Darrah, C., Pennington, C., Edwards, D.R., Donell, S.T. and Clark, I.M. (2002) The role of chondrocyte senescence in osteoarthritis. Aging Cell, 1. pp. 57-65.
Young, D.A., Philllips, B.W., Lundy, C., Nutall, R.K., Hogan, A., Schultz, G.A., Leco, K.J., Clark, I.M. and Edwards, D.R. (2002) Identification of an initiator-like element essential for the expression of the tissue inhibitor of metalloproteinases-4 (Timp-4) gene. Biochemical Journal, 364. pp. 89-99.
Wilkinson, JM, Jones, ER, Riley, GP, Chojnowski, AJ and Clark, IM (2012) The Expression of Collagen-Degrading Proteases Involved in Dupuytren’s Disease Fibroblast-Mediated Contraction. In: Dupuytren’s Disease and Related Hyperproliferative Disorders. UNSPECIFIED, pp. 143-149.
Rodgers, UR and Clark, IM (2010) Expression of Recombinant MMP-28 in Mammalian Cells. In: Matrix Metalloproteinase Protocols. UNSPECIFIED, pp. 55-65.
Clark, I.M. and Murphy, G. (2004) Matrix proteinases. In: EPRINTS-BOOK-TITLE. Academic Press.
Clark, I.M., Thomas, M.D. and de Vos, S. (2002) Plant matrixins. In: EPRINTS-BOOK-TITLE. Academic Press, pp. 570-572.
Clark, IM, Macgregor, AJ and Donell, ST (2008) Editorial-The genetic association between asporin and osteoarthritis. Working Paper. UNSPECIFIED.
Clark, I.M., Young, D.A. and Edwards, D.R. (2003) TIMP-1 enhancer sequence: real or bacterial. Working Paper. UNSPECIFIED.
WIlliams, F, Davidson, R, Skinner, J, Culley, K, Bao, YP, Cassidy, A, Clark, I and Macgregor, A (2009) Epidemiological and Molecular Evidence for the Chondroprotective Effect of Garlic in Osteoarthritis. In: Annual Meeting of the British-Society-of-Rheumatology, 2009-04-28 - 2009-05-01, Glasgow, Scotland.
Davidson, R., Donell, S., Darrah, C., Cooper, A. and Clark, Ian (2006) Controlling proteinase gene expression osteoarthritis. In: UNSPECIFIED. (Unpublished)
Clark, IM, Rowan, AD and Young, DA (2010) Matrix metalloproteinase protocols 2nd Edition. Medthods in Molecular Biology . Springer (Humana Press). ISBN 978-1-60327-298-8
Clark, I.M. (2001) Matrix Metalloproteinase Protocols. Humana Press, Totowa, New Jersey, USA.
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