Bristol Medical School: Translational Health Sciences

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Osteoarthritis Group

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Main research topics

Osteoarthritis (OA) is the most common joint disease affecting over 100 million people in the European Union countries. The disease frequently affects the hip, knee, spine and finger joints. It is characterised by abnormal changes within major joint tissues such as cartilage and bone (Figure 1a & b). At early stages of OA there is focal loss of cartilage (Figure 1a) which becomes more widespread as the disease progresses resulting is cartilage loss from whole of the joint surface. This is seen in plain x-ray as joint space narrowing (Figure 1b) and used to confirm the diagnosis of OA. OA is a major cause of pain and disability in older people for which currently there is neither a cure nor an effective treatment to stop the disease worsening. The only available treatments are pain relief and joint replacement surgery. Our research has identified new means for diagnosing and monitoring the progression of joint destruction in OA that could ultimately lead to new treatment methods for this very common joint disease.

Our research has been funded by the NHS Executive R&D Directorate, Arthritis Research Campaign and a number of collaborative pharmaceutical companies over the last ten years. During this period we have used varieties of joint-specific molecules called ‘biomarkers’ of joint disease to investigate what causes and drives the joint destruction in OA. Our long-term studies of patients with early and established OA have led to identification of several serum and urinary biomarkers which may have potential diagnostic value and can be used to monitor progression of knee OA (see Poster 1). We are also studying genetic markers that might be more specific for diagnosis of OA. The results of these studies bring the goal of developing simple 'blood tests' for OA one step closer and offer the possibility of early diagnosis and more effective management of patients with OA. Such blood tests for OA will also help to screen normal population and therefore help the NHS to better plan their expenditure in this area and target treatments more effectively.

One of our major contributions to the field is the demonstration that progression of knee OA depends on phases of disease activity that affect cartilage, bone and synovium and involve a varying balance of tissue degradation and repair (see Poster 2). This observation led us to suggest that patients will benefit more when treatment is targeted to specific a tissue or given during the active phase of the disease. Early results of clinical trials indicate that patients show better response to treatment when non-steroidal anti-inflammatory drug (widely used to treat OA) is given during clinical and biochemical evidence of inflammation. 

My other main research interest involves studies of the mechanisms of cell death in articular cartilage and in particular the role of chondrocyte apoptosis in cartilage damage in OA. In our earlier studies we have shown that increased levels of apoptosis in articular cartilage lead to a decrease in cellularity, with obvious adverse consequences for tissue homeostasis. Recently we have shown a direct correlation between chondrocyte apoptosis and the degree of cartilage matrix damage (see Poster 3) suggesting that loss of viable cells leads to matrix degradation characteristic of OA. The aim of our current research is to delineate the role of chondrocyte apoptosis in the initiation of cartilage degradation and development of OA using both in vitro and in vivo models.

Main teaching topics

  • Pathogenesis of osteoarthritis and rheumatoid arthritis
  • Structure and function of articular cartilage and bone
  • Growth hormones and their action

Other departmental duties

  • Programme Director for Anatomical Science and Neuroscience with year in industry
  • Organiser for the musculoskeletal system element for first year medical (MBChB) course
  • Organiser for the synovial joint element for BSc (Hon) in Anatomical Science

Current research projects (publications and posters)

  • Efficacy of biomarkers in the diagnosis, prognosis and treatment of osteoarthritis and other joint disease
  • Role of genetic polymorphisms in initiation and progression of osteoarthritis
  • Role of chondrocyte apoptosis in articular cartilage damage in osteoarthritis

Grants and funding

  • 2010-2013 Overseas PhD studentship from the Malaysian Ministry of Higher Education (£63000). The role of chondrocyte apoptosis in initiation and progression of osteoarthritis in spontaneous animal models of the disease (M Sharif)
  • 2007-2009 Gloucester Arthritis Trust (65842). Predicting the progression of osteoarthritis. (L Hunt, J R Kirwan, M Sharif)
  • 2005-2007 Combinatorx Clinical Trial (£115,000). A Multicenter, randomised, single-blind study comparing the effect of CRx-102 plus DMARD therapy to that of placebo plus DMARD therapy: Serum C-reactive protein (CRP) and cytokines in subjects with Rheumatoid arthritis (J Kirwan, M Sharif)
  • 2004-2007 BBSRC Committee Studentship (~£45,000). Does chondrocyte apoptosis initiate articular cartilage degradation in osteoarthritis? (M Sharif )
  • 2004-2006 Arthritis and Rheumatism Council (£61,298). 'Sequential measurements of biomarkers over 5 years in patients with knee osteoarthritis'. ( Sharif M, Kirwan)
  • 2001-2005 NHS Executive South West R&D Directorate Career Scientist Award (£160,018). 'Use of biomarkers in classifying, treating and preventing the secondary progression of osteoarthritis'. (Sharif M)
  • 2003 Arthritis Research Campaign (£15,000). Equipment grant for a LightCycler, Real Time PCR machine (D Bates, M Perry, L Donaldson, N Williams, L Handerson, M Sharif)
  • 2002-2004 The Frances and Augustus Newman Foundation (£30,152). Role of genetic polymorphisms in osteolysis around joint implants (M Perry, M Sharif, J Bidwell, Learmonth ID)
  • 2001-2002 F. Hoffmann-La Roche Ltd, Switzerland (£27,000). Biomarkers for OA and RA. (M Sharif, J Kirwan)
  • 2001-2005 NHS Executive South West R&D Directorate Career Scientist Award (£160,018). Use of biomarkers in classifying, treating and preventing the secondary progression of osteoarthritis. (M Sharif)
  • 1999-2003 F. Hoffmann-La Roche Ltd, Switzerland (£139,000 plus assay kits costing £40,000). Biomarkers for OA and RA. (M Sharif, J Kirwan)
  • 1999-2000 Biomatrix (£69,000). Viscosupplementation with Synvisc (Hylan G-F 20) in patients with patellofemoral osteoarthritis and anterior knee pain. (J Newman, J Kirwan, S Clarke, M Sharif)
  • 1997-1998 Bayer Corporation, USA ($11,320). Studies of biochemical markers in serum samples from patients treated with a novel inhibitor of metalloproteases. (M Sharif)
  • 1996-1997 Roussel-Hoechst, France (£15,400). Effects of hyaluronic acid NRD 101 on biochemical markers of joint tissue metabolism. (M Sharif, PA Dieppe)
  • 1996 The Wellcome Trust (£141, 485). Shared equipment grant with Division of Medicine Laboratories, University of Bristol
  • 1994-1996 Arthritis & Rheumatism Council (£38,684). Synovial mass, cartilage turnover and agalactosyl IgG in the Arthritis & Rheumatism Council low dose steroid study. (J R Kirwan, M Sharif)
  • Poster 2. Surrogate biomarkers for diagnosis of knee osteoarthritis (Office document, 1,385kB)
  • Poster 3. Longitudinal study of serum cartilage oligometris martix protein (COMP) and phasic progression of knee osteoarthritis (Office document, 180kB)
  • Poster 4. Evidence for significant associations between chondrocyte apoptosis and the macroscopic and microscopic appearance of articular cartilage (Office document, 4,958kB)
  • Poster 5. Longitudinal study of cartilage and subchondral bone changes in a spontaneous animal model of knee OA (Office document, 3,203kB)

Key publications

  • de Seny D*, Sharif M*, Fillet M, Cobraiville G, Meuwis MA, Marée R, Hauzeur JP, Wehenkel L, Louis E, Merville MP, Kirwan J, Ribbens C and Malaise M (2011). Discovery and biochemical characterization of four novel biomarkers for osteoarthritis. Ann Rheum Diseases 2011;70:1144-1152. Doi:1136/ard.2010.135541. * Equally contributed
  • Mahoney DJ, Swales C, Athanasou NA, Bombardieri M, Pitzalis C, Kliskey K, Sharif M, Day AJ, Milner CM, Sabokbar A. TSG-6 inhibits osteoclast activity via an autocrine mechanism and is functionally synergistic with osteoprotegerin. Arthritis Rheum. 2011 Apr;63(4):1034-43. doi: 10.1002/art.30201
  • Zamli Z and Sharif M, Chondrocyte apoptosis: a cause or consequence of osteoarthritis? Int J Rheum Dis. 2011 May;14(2):159-66. (Editorial).
  • Thomas CM, Fuller CE, Whittles CE and Sharif M (2011). Chondrocyte death by apoptosis is associated with the initiation and severity of articular cartilage degradation. Int J Rheum Dis. 2011 May;14(2):191-8. doi: 10.1111/j.1756-185X.2010.01578.x. Epub 2010 Oct 26.
  • Thomas CM, Whittles CE, Fuller CJ, Sharif M (2011).Variations in chondrocyte apoptosis may explain the increased prevalence of osteoarthritis in some joints. Rheumatology International. Rheumatol Int. 2011 Oct;31(10):1341-8. Epub 2010 Apr 16.
  • CR Davis, J Karl, R Granell, JR Kirwan, J Fasham, J Johansen, P Garnero, and M Sharif. Can biochemical markers act as surrogates for imaging in knee osteoarthritis? Arthritis and Rheumatism 2007, 56:4038-4047.
  • CM Thomas, CJ Fuller, CE Whittles & M Sharif. Chondrocyte death by apoptosis is associated with cartilage matrix degradation. Osteoarthritis and Cartilage, 2007, 15:27-34.
  • M Sharif, J R Kirwan, CJ Elson, R Granell, S. Suggestion of nonlinear or phasic progression of knee osteoarthritis based on measurements of serum cartilage oligomeric matrix protein levels over five years. Arthritis and Rheumatism 2004, 50:2479-2488.
  • Sharif M, Whitehouse A, Sharman P, Perry M, Adams M. Increased apoptosis in human osteoarthritic cartilage corresponds to reduced cell density and to expression of caspase-3. Arthritis and Rheumatism 2004, 50:507-515.
  • Clements KM, Adams MA, Crossingham GV, Bee ZC and Sharif M. At what level of stress does cyclic mechanical loading begin to kill chondrocytes? Osteoarthritis and Cartilage 2001,9:499-507. 
  • Sharif M, Salisbury C, Taylor DJ and Kirwan J. Changes in biochemical markers of joint tissue metabolism in a randomised controlled trial of glucocorticoid in early rheumatoid arthritis. Arthritis Rheum 1998; 41: 1203-1209.
  • Sharif M, Osborne DJ, Meadows K, Woodhouse SM, Colvin EM, Dieppe PA. The relevance of chondroitin and keratan sulphate markers in normal and arthritic synovial fluid. Brit J Rheum 1996; 35: 951-957.
  • Sharif M, George E, Shepstone L, Knudson W, Thonar J-MA, Cushnaghan J and Dieppe P. Serum hyaluronic acid level as a predictor of disease progression in osteoarthritis of the knee. Arthritis Rheum 1995b; 38: 760-767.
  • Sharif M, George E and Dieppe P. Correlation between synovial fluid markers of cartilage and bone turnover and scintigraphic scan abnormalities in osteoarthritis of the knee. Arthritis Rheum 1994; 38: 78-81.
  • Sharif M, Worral JG, Singh B, Gupta R, Lydyard P, Lambert C, McCulloch J and Rook GAW. Development of monoclonal antibodies to the human mitochondrial 60KD heat shock protein, and their use to study expression of the protein in rheumatoid arthritis. Arthritis Rheum 1993; 35: 1427-1433.

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