Centre for Musculoskeletal Science

Centre for Musculoskeletal Science  

The Centre for Musculoskeletal Science (CMS) is a highly successful collaborative team of scientists and clinicians from UWS and the University of Glasgow who form a thriving scientific research environment with direct clinical links. The group focus is on regulatory mechanisms and their disturbance during chronic inflammatory diseases, and in development and evaluation of novel drug therapies. Main research themes include arthritis and chronic obstructive pulmonary disease.

Facebook Page:  www.facebook.com/Centre-for-Musculoskeletal-Science-859188470803555

Twitter:  @cms_uws

Arthritis

Osteoarthritis (OA) is a very common and painful condition that affects joints like hips, knees, hands and feet. It occurs when soft protecting tissue thins and roughens, compromising the natural cushion that normally separates the ends of bones.  This degenerative disease represents a significant unmet medical need - joint replacement and other treatment is a major drain on health services around the world, and the condition has a considerable negative impact on quality of life for hundreds of millions of people. There is as yet no way of curing osteoarthritis.  For decades it’s been accepted that cartilage deteriorates with age, leading to stress on the bone. One revolutionary finding by our UWS team is that in many cases the bone changes before the cartilage – which casts an entirely different perspective on OA. Research on protease-activated receptors (PARs) and the role they play are leading to significant breakthroughs in our understanding of the disease.

UWS researchers, as part of a consortium of universities, have been awarded a £1.2 million programme grant from Versus Arthritis to bring together, for the first time, experts across 5 universities in bone, matrix, molecular and systems biology in a concerted effort to better understand osteoarthritis – particularly in dissecting what role the matriptase-PAR2 axis contributes to OA pathogenesis.

Chronic Obstructive Pulmonary Disease (COPD)

COPD is an incurable and progressive lung condition characterised by progressive airflow reduction, breathing difficulties and irreversible lung damage – and ranks as the 3^rd leading cause of death world-wide.  Despite the high prevalence of COPD and associated mortality and morbidity within Scotland and in both Ireland and Northern Ireland, there has been insufficient research focus in this field.  Funded by €7.7m Interreg VA funding from the Special EU Programmes Body, our partnered initiative to combat COPD in these regions has established a new research training hub – the Borders Regions Airways Training Hub (BREATH). Within BREATH we have brought together 50 researchers (including 19 PhD students) to investigate key aspects of COPD pathology including airway epithelial and smooth muscle dysfunction, focusing on novel roles for PARs.  http://breath-copd.org

Our collective research programmes span from fundamental to clinical levels. We collectively work within laboratory and hospital facilities at:

• Arthritis: University of the West of Scotland, University of Glasgow and University of Strathclyde, tailored specifically for research into rheumatoid and osteoarthritis at both molecular, cellular and systems levels.
• COPD: University of the West of Scotland, University of Glasgow (Prof Goodyear, Prof Ramage, Queen’s University Belfast, Dundalk Institute of Technology and University of Edinburgh (Dr Emmerson) in conjunction with NHS Ayrshire & Arran, NHS Dumfries & Galloway and NHS Greater Glasgow & Clyde.

Key Project Summaries

• Multi-tissue injury in post-traumatic arthritis
  • We have recently developed a novel disease model of post-traumatic arthritis exhibiting multi-tissue joint injury, which offers a robust system for the investigation of multiple hallmarks of osteoarthritis pathology.
• Protease-Activated Receptors (PARs) in osteo- and rheumatoid arthritis
  • We have demonstrated a key role for PAR2 in models of both rheumatoid arthritis and osteoarthritis, confirmed this in humans via translational studies, and now are dissecting the mechanism of this role on inflammatory pathways (including pain) and both bone and cartilage biology. We investigate PAR2 as a potential new therapeutic target in arthritis, and evaluate new treatment approaches.
• Role of Extracellular Vesicle in Osteoarthritis
  • We have isolated and characterised extracellular vesicles (EV) from OA synovial membrane, and shown that EV are able to drive inflammatory and remodelling changes in cartilage and primary OA chondrocytes, indicating a novel regulatory mechanism relevant to joint pathology. Importantly we have been able to show that these EV carry novel miRNA signatures which we are investigating putative roles for in joint inflammation and cartilage erosion.
• Angiotensin AT1 Receptor in chronic arthritis
  • The angiotensin system has recognised pro-inflammatory roles that we have reported contribute to OA pathogenic mechanisms; moreover, blockade of AT1 receptors partly corrects the joint vascular dysfunction associated with chronic arthritis

• BREATH (COPD) Projects
  • Role of PAR2 in regulating lung epithelial autophagy
  • PAR2 and serine proteinases in COPD
  • Elucidating the role of PAR2 in airway smooth muscle function
  • Cytotoxic effects of air pollutants on lung epithelia
  • Development and characterisation of a multi-species COPD biofilm
  • PAR2-transient receptor potential channel interactions in lung epithelia
  • Oxidative Stress Driven Inflammatory Responses in Lung Epithelial Cells

Key Publications 

• Ariiffin SM, Bennett D, Ferrell WR, Lockhart JC, Dunning L, Clements DN, Lascelles BD, Tengku Ibraham TA, Johnston P. Protease activated receptor 2 and matriptase expression in the joints of cats with and without osteoarthritis. J Feline Med Surg  DOI: 10.117/1098612X20977796 
• Asghar S, Litherland GJ, Lockhart JC, Goodyear CS, Crilly A. Exosomes in intracellular communication and implications for osteoarthritis (OA).  Rheumatology 2020 59:57-68.  DOI: 1093/rheumatology/kez462 

• McCulloch K, Huesa C, Huesa C, Dunning L, Litherland G, Crilly A, Van ‘T Hof RJ, Lockhart JC*, Goodyear CS. Accelerated post traumatic osteoarthritis in a dual injury murine model.  Osteoarthritis & Cartilage 2019 27(12):1800-1810. DOI: 3389/fendo.2018.00257. Epub 2019 Jul 5. 
• Macdonald CD, Falconer AMD, Chan CM, Wilkinson DJ, Skelton A, Reynard L, Litherland GJ, Europe-Finner GN, Rowan AD. Cytokine-induced cysteine- serine-rich nuclear protein-1 (CSRNP1) selectively contributes to MMP1 expression in human chondrocytes. PLoS One. 2018; 13(11):e0207240. doi: 10.1371/journal.pone.0207240. 
• Baker J, Falconer AMD, Wilkinson DJ, Europe-Finner GN, Litherland GJ, Rowan AD. Protein kinase D3 modulates MMP1 and MMP13 expression in human chondrocytes. PLoS One. 2018; 13(4):e0195864. doi: 10.1371/journal.pone.0195864. 
• McCulloch K, McGrath S, Huesa C, Dunning L, Litherland G, Crilly A, Hultin L, Ferrell WR, Lockhart JC, Goodyear CS. Rheumatic Disease: PAR2 in Synovial Joint Pathobiology.  Frontiers in Endocrinology (Bone Research) 2018 9:1-7. DOI: 1016/j.joca.2019.05.027  
• Wilkinson D, Desilets A, Lin H, Charlton S, Arques M, Falconer A, Bullock C, Hsu Y, Birchall K, Hawkins A, Thompson P, Ferrell WR, Lockhart J, Plevin R, Zhang Y, Blain E, Lin S, Leduc R, Milner J, Rowan AD. The serine proteinase hepsin is an activator of pro-matrix metalloproteinases: molecular mechanisms and implications for extracellular matrix turnover.  Scientific Reports 2017 7: 1-38. DOI: 1038/s41598-017-17028-3 

• Hamilton K, Dunning L, Ferrell WR, Lockhart JC, MacKenzie A. Endothelium-derived contraction in a model of rheumatoid arthritis is mediated via angiotensin II type 1 receptors. Vascular Pharmacology 2018 100:51-57. https://doi.org/10.1016/j.vph.2017.11.001 https://www.sciencedirect.com/science/article/pii/S1537189117302653 
• McCulloch K, Litherland GJ, Rai TS. Cellular senescence in osteoarthritis pathology. Aging Cell. 2017; 16(2):210-218. doi: 10.1111/acel.12562. 
• Huesa C, Ortiz AR, Dunning L, McGavin L, Bennett L, McIntosh K, Crilly A, Kurowska-Stolarska M, Plevin R, van ’t Hof RJ, Rowan AD, McInnes IB, Goodyear CS, Lockhart JC*, Ferrell WR. Proteinase-activated receptor 2 modulates OA related pain, cartilage and bone pathology.  Ann Rheum Dis 2016; 75(11):1989-1997.  doi:10.1136/annrheumdis-2015-208268  (highlighted in Nature Reviews Rheumatology doi:10.1038/nrrheum.2016.6) 
• Litherland GJ, Hui W, Elias MS, Wilkinson DJ, Watson S, Huesa C, Young DA, Rowan AD. Glycogen synthase kinase 3 inhibition stimulates human cartilage destruction and exacerbates murine osteoarthritis. Arthritis Rheumatol. 2014; 66(8):2175-87. doi: 10.1002/art.38681. 
• Mackenzie A, Dunning L, Ferrell WR, Lockhart JC. Angiotensin II type 1 receptor blockade protects endothelium-derived hyperpolarising factor–mediated relaxation in a rat model of monoarthritis.  Life Sci 2013 92:1131-7. 

• Steven R, Crilly A, Lockhart JC, Ferrell WR, McInnes IB. Proteinase activated receptor-2 modulates human macrophage differentiation and effector function.  Innate Immunity 2013;19(6):663-72. 
• Crilly A, Palmer HS, Nickdel MB, Dunning L, Lockhart JC, Plevin R, McInnes IB, Ferrell WR. Immunomodulatory role of proteinase-activated receptor-2 in collagen-induced arthritis. Ann Rheum Dis 2012; 71: 1559-66.             doi:10.1136annrheumdis-2011-200869 
• Crilly A, Burns E, Nickdel MB, Lockhart JC, Perry ME, Ferrell PW, Baxter D, Dale J, Dunning L, Wilson H, Nijjar JS, Gracie JA, Ferrell WR, McInnes IB. PAR2 expression in peripheral blood monocytes of patients with rheumatoid arthritis.  Ann Rheum Dis 2012; 71: 1049-54. doi:10.1136/annrheumdis-2011-200703 
• Tindell AG, Kelso EB, Ferrell WR, Lockhart JC, Walsh DA, McInnes IB. Protease-Activated Receptor-2 expression is strongly correlated with synovitis in rheumatoid and osteoarthritis. Rheumatology International 2012; 32: 3077-86.  DOI 10.1007/s00296-011-2102-9 
• Ferrell WR, Kelso EB, Lockhart JC, Plevin R, McInnes IB: Protease-activated receptor-2: a novel pathogenic pathway in a murine model of osteoarthritis.  Ann Rheum Dis 2010; 69: 2051-2054.  

• 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, Rowan AD: Matriptase is a novel initiator of cartilage matrix degradation in osteoarthritis. Arth Rheum 2010; 62(7): 1955-66. 
• McIntosh K, Cunningham MR, Candalbert L, Lockhart JC, Boyd G, Ferrell WR, Plevin R: Proteinase-activated receptor-2 mediated inhibition of TNFa-stimulated JNK activation – a novel paradigm for Gq/11 linked GPCRs.  Cellular Signalling 2010; 22(2): 265-273.  
• Ferrell WR, Lockhart JC, Plevin R: Proteinase-activated receptor-2 (PAR-2): a potential new target in arthritis.  Drugs for the Future 2008; 33(3): 1-8.  
• Perry ME, Chee MM, Ferrell WR, Lockhart JC, Sturrock RD: Angiotensin receptor blockers reduce ESR levels in rheumatoid arthritis patients (letter). Ann Rheum Dis 2008; 67(11): 1646-7.  
• Palmer HS, Kelso EB, Lockhart JC, Sommerhoff CP, Plevin R, Goh FG, Ferrell WR: Proteinase-activated receptor-2 (PAR2) mediates the pro-inflammatory effects of synovial mast cells.  Arth Rheum 2007; 56(11): 3532-3540. 

• Ferrell WR, Lockhart JC, Kelso EB, Dunning L: Evaluation of protease-activated receptor 2 in murine models of arthritis: comment on the article by Busso et al. [letter].  Arth Rheum 2007; 56(10): 3510. 
• McIntosh KA, Plevin R, Ferrell WR, Lockhart JC: The therapeutic potential of proteinase-activated receptors in arthritis.  Curr Op Pharmacol 2007; 56(3): 765-771. 
• Kelso EB, Ferrell WR, Lockhart JC, Elias-Jones I, Hembrough T, Dunning L, Gracie JA, McInnes IB: Expression and pro-inflammatory role of proteinase-activated receptor 2 in rheumatoid synovium: ex vivo studies suing a novel proteinase-activated receptor-2 antagonist.  Arth Rheum 2007; 56(3): 765-771. 
• Price A, Lockhart JC, Ferrell WR, Chee MM, Perry M, Gsell W, McLean S, Sturrock RD: Angiotensin AT1 receptor as a novel therapeutic target in rheumatoid arthritis.  Arth Rheum 2007; 56(2): 441-447. 
• Kelso EB, Lockhart JC, Hembrough T, Dunning L, Plevin R, Hollenberg MD, Sommerhoff CP, McLean JS, Ferrell WR: Therapeutic promise of PAR2 antagonism in joint inflammation.  J Pharmacol Exp Ther 2006; 316: 1017-1024.  

• Kane D, Lockhart JC, Balint PV, Mann C, Ferrell WR, McInnes IB: Protective effect of sensory denervation in inflammatory arthritis (evidence of regulatory neuro-immune pathways in the arthritic joint).  Ann Rheum Dis 2005; 64: 325-327.  
• Egan CG, Lockhart JC, Ferrell WR: Pathophysiology of vascular dysfunction in a rat model of chronic joint inflammation. J Physiol 2004; 557: 635-644. 
• Day SM, Lockhart JC, Ferrell WR, McLean JS: Divergent roles of nitrergic and prostanoid pathways in chronic joint inflammation.  Ann Rheum Dis 2004; 63, 1564-1570. 
• Ferrell WR, Lockhart JC, Kelso EB, Dunning L, Plevin R, Meek SE, Smith AJH, Hunter GD, McLean JS, McGarry F, Ramage R, Jiang L, Kanke T, Kawagoe J: Essential role for proteinase activated receptor-2 in arthritis.  J Clin Invest 2003; 111: 35-41. 

Partners

• Cross Party Group on Lung Health – parliament.scot/msps/lung-health.aspx
• Teva UK – tevauk.com
• Chiesi – chiesi.uk.com
• AstraZeneca – astrazeneca.com
• GlaxoSmithKline – gsk.com
• NHS Trusts]
  • Greater Glasgow & Clyde – nhsdg.co.uk
  • Ayrshire & Arran – nhsaaa.net
  • Dumfries & Galloway – nhsggc.org.uk
  • Belfast Trust HSCNI – hscni.net
• District Councils
  • Ayrshire Councils – north-ayrshire.gov.uk; www.east-ayrshire.gov.uk; www.south-ayrshire.gov.uk
  • Dumfries & Galloway – dumgal.gov.uk
• British Lung Foundation – blf.org.uk
• Chest Heart & Stroke Scotland – chss.org.uk
• Glasgow Science Festival – glasgowsciencefestival.org.uk

Universities

University of Glasgow

University of Strathclyde

University of Edinburgh

University of Liverpool

University of Newcastle

Queen’s University Belfast

Dundalk Institute of Technology

NHS Greater Glasgow & Clyde

NHS Ayrshire & Arran

NHS Dumfries & Galloway