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.
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.
- Arthritis Research Campaign
- Alzheimer’s Research Fund
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.
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.
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.
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.
Visiting Clinical Fellow
Mrs Amy Morgan
Dr Helen Roberts