RAGE and activation of chrondrocytes and fibroblast-like synoviocytes in joint diseases

Steenvoorden, M.M.C. (2007)

Doctoral Thesis

This dissertation describes a new model in which cartilage degradation can be studied. New cartilage is formed by bovine chondrocytes obtained from the slaughterhouse and cocultured with synovial cells from rheumatoid arthritis (RA) patients to study the interaction between the chondrocytes and synoviocytes.The results of our study show that the role of synoviocytes in cartilage degradation is dependent on the presence of live chondrocytes. In osteoarthritis (OA) patients an increased level of advanced glycation endproducts (AGEs), which can bind to the receptor for AGEs (RAGE), is found in the cartilage. In RA patients, increased levels of AGEs and other RAGE-binding proteins is found in serum, synovial tissue and –fluid. We therefore studied the effect of RAGE activation on chondrocytes and synoviocytes from OA and RA patients and found that both chondrocytes and synoviocytes become more active and start to degrade cartilage. Blockade of RAGE activation might therefore be an interesting target in treatment of OA and RA patients. The synoviocytes in RA synovial tissue have an altered, aggressive phenotype and can degrade cartilage. Hereby, they share properties of fibrotic/tumorigenic cells. We found that healthy synoviocytes are epithelial-like cells and that synovial fluid from RA patients will induce a change in phenotype and production of proteins found in fibrotic/tumorigenic cells. BMP-7, a protein able to induce cartilage production by chondrocytes, is able to inhibit this change in phenotype and might therefore be an interesting target to prevent the alteration of synoviocyte phenotype.

• Cartilage degradation
• Chondrocytes
• Fibroblast-like synovioyctes
• Epithelial to mesenchymal transition
• HMGB-1
• Osteoarthritis
• RAGE
• Rheumatoid arthritis

• All authors: Steenvoorden, M.M.C.
• Supervisor: Huizinga, T.W.J.
• Co-supervisor: Groot, J. de; Toes, R.E.M.
• Qualification: Doctor (dr.)
• Awarding Institution: Department Reumatology, Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
• Date: 2007-02-01
• ISBN (print): 9789085592518
• Court: LEI Universiteit Leiden
• Sponsorship: TNO Quality of Life, the Dutch Arthritis Association, ZonMW, the Dr. Ir. Van de Laar Stichting and the Jurriaanse Stichting