Prof Bruce Caterson - PhD
Figure1: Monoclonal Antibodies to GAG sulphation Motif Epitopes and Neoepitopes on Aggrecan, Aggrecanase-generated Catabolites and Link Protein
Over the past 27 years Professor Bruce Caterson’s research has focussed on the production, development and use of monoclonal antibody (mAb) technologies for studies of connective tissue proteoglycan metabolism in health and disease. These studies have focussed on matrix proteoglycan metabolism in musculoskeletal tissues with a particular emphasis on studies involving molecular mechanism underlying the pathogenesis of degenerative joint diseases; i.e. osteoarthritis and rheumatoid arthritis. Our lab has now developed and characterised numerous mAbs that recognise both carbohydrate and protein epitopes and neoepitopes that are present on proteoglycans in all connective tissues throughout the body (see Figure 1 and publications, as recent examples). Many of these mAbs are now commercially available to researchers worldwide.
Figure 2:
Immunochemical identification of stem/progenitor cells in the surface/superficial zone of articular cartilage: Immunohistochemical localisation of cell surface and matrix proteoglycans containing native chondroitin sulphate (CS) glycosaminoglycan (GAG) sulphation motifs recognised by monoclonal antibodies 4-C-3(-) and 7-D-4(-). These antibodies identify the pericellular environment surrounding stem/progenitor cells located in the surface/superficial zone of 7-day old bovine articular cartilage. Antibody 4-C-3(-) also recognises CS on proteoglycans surrounding cells (pericytes?) in small blood vessels located in the calcified zone of the immature cartilage.
These reagents and technologies are also being applied to development of new antibody-based biomarker assays to diagnose and monitor the efficacy of therapeutic or surgical interventions in the treatment of degenerative joint diseases and changes in matrix proteoglycan and protein metabolism associated changes in the peri-neuronal net in the pathogenesis of Alzheimer’s disease. Furthermore, these mAb technologies have been applied to tissue engineering & tissue regeneration applications involving the repair of articular cartilage and other musculoskeletal tissues (7, 10). In recent years, these research interests have extended to several collaborative studies investigating proteoglycan metabolism and extracellular matrix organisation in the cornea of the eye during development and with the onset of pathology (2, 4). Very recent work (10) has used several monoclonal antibodies that recognise chondroitin sulphate (CS) glycosaminoglycan sulphation motifs to identify stem/progenitor cells in their “stem cell niches” of musculoskeletal tissues (i.e. cartilage, tendon and intervertebral disc), the eye and the gut of several different animal species (see Figures 2 above & 3 below).
Figure 3:Chondroitin sulphate (CS) glycosaminoglycan (GAG) sulphation motifs and the “stem/progenitor cell niche”:(A) Hyaluronan (HA) bound to CD44 and minimally sulphated CS GAG chains occur on cell surface and matrix proteoglycans and form a protective barrier around stem/progenitor cells in the tissue matrix. These lowly sulphat'ed CS proteoglycans and HA have a low affinity for binding and/or presentation of growth factors, cytokines and chemokines to the dormant stem/progenitor cell. However, many of these growth factors are sequestered on more abundant and highly sulphated CS GAG chains in the territorial and extracellular matrix of the tissue; (B) After being presented with an activating stimulus (e.g. mechanical stress, matrix depletion), the stem/progenitor cell is stimulated to divide and produce two daughter cells. This division physically pushes one of the daughter cells out into the territorial matrix where its cell surface receptors can now interact with growth factors & chemokines already bound to more highly sulphated CS and other GAGs with conformations favourable for receptor binding. (C) These interactions with cell surface receptors stimulate this one daughter cell to proliferate and further differentiate down a chondrocytic lineage. The other daughter cell remains in the “stem/progenitor cell niche” protected from stimulation by growth factors, cytokine and chemokines by the lesser sulphated CS GAGs on proteoglycan and hyaluronan bound to CD44 surrounding this still naive stem/progenitor daughter cell.
Recent Publications (2006-present)
- Grau S., Richards, P.J., Kerr, B., Hughes, C.E., Caterson, B., Williams, A.S., Junker, U., Jones, S.A., Clausen, T, Ehrmann M. (2006). The role of human HtrA1 in arthritic disease. J. Biol. Chem. 281:6124-6129
- Hayashida Y., Akama, T.O., Beecher, N., Lewis, P., Young, R.D., Meek, K.M., Kerr, B., Hughes, C.E., Caterson, B., Tanigami, A., Nakayama, J.,Fukada, M.n>, Tano, Y., Nishida, K. & Quantok, A.J. (2006). Matrix morphogenesis in cornea is mediated by the modification of keratan sulfate by GlcNAc 6-O-sulfotransferase. Proc. Natl. Acad. Sci. USA 103: 13333-13338
- Jones A.R., Gleghorn, J.P., Hughes, C.E., Fitz, L.J., Zollner, R., Wainwright, S.D., Caterson, B., Morris, E.A., Bonassar, L.J. & Flannery, C.R. (2007). Binding and localization of recombinant lubricin to articular cartilage surfaces. J. Orthop. Res. 25: 283 – 292
- Young, R.D., Akama, T.O., Liskova, P., Ebenezer, N.D.,Allan, B., Kerr, B, Caterson, B., Fukada, M.N. & Quantok, A.J. (2007). Differential immunogold localisation of sulphated and unsulphated keratan sulphate proteoglycans in normal and macular dystrophy cornea using sulphation motif-specific antibodies. Histochem. Cell Biol. 127:115-20
- Bondeson, J., Lauder, S., Wainwright, S., Amos, N., Evans, A., Hughes, C.E., Feldman, M. & Caterson, B. (2007). Adenoviral gene transfer of the endogenous inhibitor I k B a into human ostroarthritis synovial fibroblasts demonstrates that several matrix metalloproteinases and aggrecanases are nuclear factor dependent. J. Rheumatol. 34(3):523-33
- Rees, SG, Waggett AD, Dent, CM & Caterson B. (2007). Inhibition of aggrecan turnover in short-term explant cultures of bovine tendon. Matrix Biology 26: 280 - 290
- Hayes AJ, Hall A, Brown L, Tubo R, Caterson B. (2007). Macromolecular Organization and In Vitro Growth Characteristics of Scaffold-free Neocartilage Grafts. J Histochem Cytochem. 55: 853 - 866
- Gendron C, Kashiwagi M, Lim NH, Enghild JJ, Thogersen IB, Hughes C, Caterson B, Nagase H. (2007). Proteolytic activities of human ADAMTS-5: Comparative studies with human ADAMTS-4. J Biol Chem. 282: 18294 – 18306
- Cao J, Li S, Shi Z, Yue Y, Sun J, Chen J, Fu y Q , Hughes CE and Caterson B (2007). Articular cartilage metabolism in patients with Kashin-Beck Disease: an endemic osteoarthropathy in China. Osteoarthritis and Cartilage “in press”
- Gealy EC, Kerr BC, Young RD, Tudor D, Hayes AJ, Hughes CE, Caterson B, Quantock AJ & Ralphs JR(2007). Differential expression of the keratan sulphate proteoglycan, keratocan, during chick corneal embryogenesis. Histochem Cell Biol. 128(6):551-555.
- Young RD, Gealy EC, Liles M, Caterson B, Ralphs JR & Quantock AJ (2007). Keratan sulfate glycosaminoglycan and the association with collagen fibrils in rudimentary lamellae in the developing avian cornea. Invest Ophthalmol Vis Sci. 48(7):3083-3088
- Hayes AJ, Tudor D, Nowell M, Caterson B and Hughes CE (2007). Chondroitin Sulfate Sulfation Motifs As Putative Biomarkers for Isolation of Articular Cartilage Progenitor Cells. J. Histochem. Cytochem 55: “in press”
- Khan IM, Gilbert SJ, Caterson B, Sandell LJ and Archer CW (2007). Oxidative stress induces expression of osteoarthritis markers, procollagen 2A and 3-B-3(-) in adult bovine articular cartilage. Osteoarthritis & Cartilage “in press
Current Funding
- Arthritis Research Campaign
- BBSRC
- EPSRC
- Alzheimer’s Research Fund
- Industry
Funded Collaborations
Cardiff University
Professor John L. Harwood, Head of School, School of Biosciences: Effects of n-3 fatty acids on brain peri-neuronal net metabolism in the pathogenesis of Alzheimer’s disease.
Mr Colin Dent, FRCS (Orth), Professor of Orthopaedics & Trauma, School of Medicine: Tendon matrix proteoglycan metabolism in health and disease. Biomarkers for musculoskeletal diseases.
Professor Keith Meek and Dr Andrew Quantok, School of Optometry: Corneal matrix organisation and metabolism during development and pathology.
Professor Ruth Duncan, School of Pharmacy and Dr Peter Griffith, School of Chemistry: Nanotechnology drug delivery systems for treatment of arthritic diseases.
Professor Chris McGuigan, School of Pharmacy: The beneficial effects of chemically-modified glucosamine on cartilage metabolism in the pathogenesis of osteoarthritis.
Dr Jan Bondeson, Rheumatology, School of Medicine: Regulation of aggrecanases and matrix metalloproteinase expression in the pathogenesis of degenerative joint diseases.
Dr Jim Ralphs, School of Biosciences: Corneal matrix organisation during development.
National
Dr Sally Roberts & Professor James B. Richardson, RJAH Orthopaedic Hospital, Oswestry: Biomarkers for degenerative joint and disc disease.
Professor Richard Oreffo, Department of Orthopaedics, University of Southhampton: Glycosaminoglycan and polymer scaffolds for tissue engineering and regeneration.
Dr Sarah G. Rees, School of Medicine, Swansea University: Tendon proteoglycan metabolism in health and disease.
International
Dr Virginia Kraus, Department of Rheumatology, Duke University, Durham, NC, USA: Biomarkers of musculoskeletal diseases & cartilage metabolism in the pathogenesis of Kashin-Beck disease.
Professor Junling Cao, Institute of Endemic Diseases, Xi’an Jiaotong Medical University, Xi’an, China: Cartilage metabolism in the pathogenesis of Kashin-Beck Disease.
Dr Chris B. Little, Director, Raymond Purves Institute of Bone and Joint Research, University of Sydney, Australia: Proteoglycan metabolism in cartilage and intervertebral disc disease.
Affilliated Staff and Postgraduate Students
Senior Lecturer
Scientific Officer
Postdoctoral Researchers
Dr Claire Gealy
Dr Alison Powell
Dr Radha Nair-Roberts
Dr Debbie Tudor
Orthopaedic Surgery Registrar Trainees
Dr Rahul Kotwal
Dr Naidu Maripuri
Urological Surgery Registrar Trainees
Dr Christian Nayar
Postgraduate Students
Cecile Bascoul
Iris Cheung
Amanda Hall
Research Assistant
Amy Wright