SIGNIFICANT CORRELATION BETWEEN THROMBOSPONDIN-1 AND SERINE PROTEINASE EXPRESSION IN RHEUMATOID SYNOVIUM

Objective. Thrombospondin 1 (TSP1) is a potent active site inhibitor o f leukocyte elastase and cathepsin G. This effect is markedly dependen t on the disulfide-bond conformation of TSP1, with one isoform, TSP1(0 .1) being the most potent, The aims of this study were to examine the expression of different disulfide-bonded isoforms of TSP1 in inflammat ory environments in which elastase and cathepsin G are present in vari able amounts, and to determine the relationship between these proteina ses and their potential inhibitor. Methods. Immunohistochemical staini ng and histomorphometric analysis were used to examine adjacent sectio ns of synovial tissue from patients with rheumatoid arthritis (RA), os teoarthritis (OA), and meniscal trauma (MT), for expression of TSP1 an d the TSP1(0.1) isoform, elastase, cathepsin G, and chymase. Results, TSP1 localized to vessels and cells within the synovium, TSP1 expressi on was highly up-regulated in RA (mean density 98 cells and vessels/mm (2), compared with 13/mm(2) in OA and 17/mm(2) in MT), The TSP1(0.1) i soform was found virtually exclusively in RA, with 44% of vascular TSP 1 staining being due to the TSP1(0.1) isoform In RA, as compared with 7% in OA (P = 0.0047). Elastase-and cathepsin G-positive cells were ab undant in RA, with mean densities of 106 cells/mm(2) and 103 cells/mm( 2), respectively, compared with 2 cells/mm(2) and 11 cells/mm(2) in OA . There was a nide range of both TSP1 and proteinase expression within the RA group, but samples containing large numbers of elastase-and ca thepsin G-positive cells also showed high expression of TSP1, especial ly TSP1(0.1). A strong correlation was found between elastase or cathe psin G densities and TSP1(0.1) expression in blood vessels (r = 0.86 a nd r = 0.76 respectively, P < 0.01). Conclusion. TSP1(0.1), with the m ost potent inhibitory activity in vitro, is specifically up-regulated in RA, and this up-regulation is in proportion to the numbers of surro unding leukocytes containing elastase and cathepsin G. One role of TSP 1 may be to act as a matrix-based regulator of leukocyte-derived serin e proteinases in vivo.