My research elucidates new signalling mechanisms that regulate bone and cartilage turnover, to provide therapeutic and diagnostic targets for osteoporosis, rheumatoid arthritis and osteoarthritis. This has led to the discovery of functional glutamatergic signalling in bone and synovium, and revealed new pathways that mediate cytokine- and mechanically- induced cartilage degradation. As a Team Leader in the Arthritis Research UK Biomechanics and Bioengineering Centre, I direct research investigating the links between pain, inflammation and pathology in human arthritis. We have developed a range of protocols and cell, explant, animal and human models to investigate how altered joint biomechanics influences biological signals.

Current research includes:

• Modulation of glutamatergic signalling to enhance bone formation and inhibit pathological changes in arthritis.
• Delineating the role of Protein Kinase R in arthritis.
• Linking biological signals to joint loading and pathology in human arthritis.
• Using Nuclear Magnetic Resonance Spectroscopy to identify complex patterns of biomarkers to stratify patients with arthritis or joint pathology.
• Developing a novel, mechanically-loaded 3D co-culture system to investigate osteocyte control of osteoblasts

Glutamate Signalling: My work implicating the glutamate transporter GLAST-1 in mechanotransduction, and identifying glutamate as a potential anabolic target in bone is leading to new strategies for increasing bone formation. Our discovery that glutamate signalling mediates pathological responses in inflammatory arthritis, and that specific glutamate receptors are expressed in human inflammatory and osteoarthritis, reveals a therapeutic opportunity whereby joint destruction and pain could be prevented using specific glutamate receptor antagonists. http://www.news-medical.net/news/20130814/Osteoarthritis-research-an-interview-with-Dr-Deborah-Mason-Cardiff-University.aspx

1. Cleo S Bonnet ¹, Anwen S Williams ², Sophie J Gilbert ¹, Ann K Harvey ³, Bronwen A Evans ⁴, and Deborah J Mason  AMPA/kainate glutamate receptors contribute to inflammation, degeneration and pain related behaviour in inflammatory stages of arthritis. Annals of Rheumatic Diseases - under review.
2. Brakspear KS and Mason DJ (2012) Glutamate signaling in bone. Front. Endocrin. 3:97.
3. Flood S, Parri R, Williams A, Duance V and Mason DJ (2007) Modulation of interleukin-6 and matrix metalloproteinase 2 expression in human fibroblast-like synoviocytes by functional ionotropic glutamate receptors. Arthritis and Rheumatism 56(8): 2523-2534.
4. Mason DJ (2004) The role of glutamate transporters in bone cell signalling. Journal of Musculoskeletal and Neuronal Interactions 4:128-131.            
5. Mason DJ (2004) Glutamate Signalling and its Potential Application to Tissue  Engineering of bone. European Cells and Materials 7:12-26. 
6. Mason DJ and Huggett JF (2002) Glutamate Transporters in Bone Journal of Musculoskeletal and Neuronal Interactions 2 (5): 406-414
7. Huggett JF, Mustafa A, O’Neal L and Mason DJ (2002) The glutamate transporter GLAST-1 (EAAT-1) is expressed in the plasma membrane of osteocytes and is responsive to extracellular glutamate concentration. Biochem Soc Trans 30:890-893.
8. Skerry T, Genever P, Taylor A, Dobson K, Mason D , Suva L. (2001) Letters to the Editor: Absence of Evidence is not evidence of absence. The shortcomings of the GLAST knockout mouse. JBMR 16 (9):1729-1730.
9. Huggett J, Vaughan-Thomas A, Mason DJ (2000) The open reading frame of the Na(+)-dependent glutamate transporter GLAST-1 is expressed in bone and a splice variant of this molecule is expressed in bone and brain. FEBS Lett 485(1):13-18.
10. Mason DJ, Suva LJ, Genever PG, Patton AJ, Steuckle S, Hillam RA, and Skerry TM (1997). Mechanically-regulated expression of a neural glutamate transporter in bone.  A role for excitatory amino acids as osteotropic agents? Bone 20 (3):199-20.

PKR and ceramide in arthritis: Protein Kinase R (PKR) mediates stress and viral responses. We reported that PKR is activated in osteoarthritis and demonstrated that PKR mediates cytokine -induced degradation of cartilage. We have also shown that ceramide, a cytokine induced second messenger, influences cartilage matrix homeostasis via ERK signalling. P58IPK inhibits PKR and PERK and knockouts of this, where PKR and PERK are overactivated, have joint degeneration that resembles osteoarthritis. These new mechanisms of cytokine mediated cartilage degradation, relevant to both osteo- and rheumatoid arthritis, may be targeted in treatment or diagnosis of arthritis.

1.  Gilbert SJ, Meakin LB, Nowell MA, Bonnet CS^, Ladiges WC, Morton J, Duance VC and Mason DJ. Deletion of P58IPK, the cellular inhibitor of the protein kinases PKR and PERK, causes bone changes and joint degeneration in mice. Osteoarthritis and Cartilage – under review.
2. Gilbert SJ, Blain EJ, Vaughan-Thomas A, Duance VC and Mason DJ (2012) Protein kinase R plays a pivotal role in the oncostatin M and interleukin-1 signalling in bovine articular cartilage chondrocytes^. European Cells and Materials, 23:41-57.
3. Gilbert SJ, Blain EJ, Duance VC and Mason DJ (2008) Sphingomyelinase decreases type II collagen expression in bovine articular chondrocytes via the ERK signalling pathway. Arthritis and Rheumatism 58:209-220.
4. Gilbert SJ, Blain EJ, Jones P, Duance VC, Mason DJ (2006) Exogenous sphingomyelinase increases collagen and sulphated glycosaminoglycan production by primary articular chondrocytes: an in vitro study. Arthritis Research and Therapy 8(4):R89
5. Gilbert SJ, Duance VC and Mason DJ (2006) Protein Kinase R: A novel mediator of articular cartilage degradation in arthritis. Current Rheumatology Reviews 2(1):9-21.     
6. Gilbert SJ, Duance VC, Mason DJ (2004) Does PKR mediate TNF alpha and ceramide induced increases in expression and activation of MMPs in articular cartilage by a novel mechanism? Arthritis Res Ther 6:46-55.
7. Gilbert SJ, Duance VC and Mason DJ (2002) Tumour necrosis factor a up-regulates protein kinase R (PKR)-activating protein (PACT) and increases phosphorylation of PKR and eukaryotic initiation factor 2-a in articular chondrocytes. Biochem Soc Trans 30:886-9.

Biomechanics: Mechanical loading is a potent stimulus regulating both formation and degradation of bone and cartilage. Our studies on the effects of mechanical loading in bone and cartilage have implicated glutamatergic signalling, degradative enzymes, and the cytoskeleton in mechanotransduction. Recently, award of the Arthritis Research UK Biomechanics and Bioengineering Centre has allowed us to investigate the molecular signals underlying joint loading, pain and inflammation in humans with osteoarthritis or joint injury.

1. JB Catterall, S Dewitt, DJ Mason, Wilson C, K Fagerlund, JM Halleen, B Caterson. CTx-II is a marker of cartilage destruction and reflects cartilage metabolism. Osteoarthritis and Cartilage - under review
2. D J Mason, ¹K Brakspear, ²C Wilson, ²R Williams, ²R S Kotwal (2010). Glutamate, a signal that links mechanical loading, pain and pathology in human arthritis. Invited paper, Computer Methods in Biomechanics and Biomedical Engineering, Porto. ISBN: 978-9562121-0-8.

Research Funding 2008-2012 (from £12M total grant funding)

Wilde (Avanticell Science Ltd), Evans BA and Mason DJ (Cardiff University) (2013-2014) A Cell-Based Analysis Platform to Screen Nutraceuticals and Functional Foods against Osteoporosis TSB £99,889

Mason DJ, Bonnet CS, Williams AS and Walsh D (2013-2016) Investigating the mechanism of the protective role of glutamate receptor antagonists in osteoarthritis. Arthritis Research UK £200,000

John A and Mason DJ (Mentor) (2012-2015)AHSC Clinical Research Time Competition. Investigate biological mechanisms and biomarkers underlying early events in adverse reactions to MoM hip implants, NISCHR £70,762

John A and Mason DJ (2012-2015) MD Investigate biological mechanisms and biomarkers underlying early events in adverse reactions to MoM hip implants, Self-funded £8,000

Nowell M,  Mason DJ, Aeschlimann D, Evans B, Choy E. (2012) 384-capacity Real-Time Quantitative Polymerase Chain Reaction (qPCR) facility. Arthritis Research UK, £ 131,115

Mason DJ andHuggett JF. (2010-2014) PhD sudentship: Development and evaluation of new standardisation methods for RNA measurement in connective tissue diseases. LGC , £84,000

Evans B, Mason DJ, Sloan A, Ralphs, Gregory. Hadwen Trust (2010- 2012) Development of new methodologies for the 3-D in vitro study of bone disease £83,000

Duance, Mason, Holt, Evans, Riccardi, Denyer, Jones, Williams, Evans, Aeschlimann, Van Deursen and Wise. Arthritis Research UK Biomechanics and Bioengineering Centre. Arthritis Research UK  2009-2014, £2.5M, matched with £7.5M from Cardiff University.

Mason DJ, Evans BAE, Riccardi, (2009-2013) PhD sudentship: Investigating the roles of adenosine, glutamate and calcium signalling in mechanically-induced bone formation. Cardiff University, £84,000

Evans BAE and Mason DJ (2010-2014) PhD sudentship: Investigating the response to load of human osteocytes from different anatomical sites in health and disease, Cardiff University, £84,000

Mason DJ, Roberts H, Paisey S, Wilson C, Fairhurst S, Bagley M, Jones G. Using NMR for synovial fluid biomarkers. Cardiff and Vale Orthopaedics Centre,Dept Orthopaedics and School of Physics, Cardiff University (2009 – 2013) £20,000

Mason DJ and Parsons P, Modulating glutamate transporters for fracture repair. BBSRC CASE  with Smith and Nephew as industrial partner, 2007-2010, £77,000.

Collaborators

External:

• Prof David Walsh (Arthritis Research UK Pain Centre, Nottingham).
• Dr Lee Meakin (Bristol University)
• Prof Ladiges and Dr John Morton (Dept Comparative Medicine, University of Washington)
• Dr Jim Huggett (Nucleic Acid Metrology Molecular & Cell Biology LGC, Middlesex)
• Prof Mark Bagley (University of Sussex)
• Prof Chris Wilson (Consultant Orthopaedic Knee surgeon in Cardiff and Vale NHS Trust)
• Mr Alun John (Consultant Orthopaedic hip surgeon in Cardiff and Vale NHS Trust)

Cardiff University:

• School of Engineering: Dr Cathy Holt, Prof Sam Evans, Dr Gemma Whatling
• School of Medicine: Dr Bronwen Evans, Dr Anwen Williams, Dr Ann Harvey
• School of Physics: Dr Stephen Fairhurst
• School of Healthcare Studies:  Dr Val Sparkes, Dr Nicky Phillips
• School of Dentistry: Dr Alistair Sloan, Dr Sharon Dewitt
• School of Biosciences: Prof Victor Duance, Dr Sophie Gilbert, Professor Daniela Riccardi and Dr Jim Ralphs

Current Research Group Members

Post Doctoral Research Associates

Dr Sophie Gilbert

Dr Cleo Bonnet

 

PhD students

Rebecca Sanders

Nicole Scully

Ahmed Almansour