Distinct expression of mast cell tryptase and protease activated receptor-2 in synovia of rheumatoid arthritis and osteoarthritis

Abstract

The objective of this study is to examine the differential expression of mast cell tryptase and its receptor, protease-activated receptor-2 (PAR-2), in the synovium and synovial fluid of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Biochemical and immunohistochemical analyses were performed to determine whether the trypsin-like protease in the synovium is identical to mast cell tryptase. The effects of mast cell tryptase on the proliferation of synovial fibroblast-like cells (SFCs) and the release of IL-8 thereof were evaluated by the [3H]-thymidine incorporation and ELISA, respectively. The trypsin-like protease in the synovium of RA patients was identical to human mast cell tryptase, which was composed of two subunits: 33 and 34 kDa. The 33- and 34-kDa proteins are different glycosylated forms of the 31-kDa protein, which was unglycosylated. Mast cell tryptase activity in RA synovial fluid was significantly higher than that in OA synovial fluid, while their activities and expression in the synovium were similar. Expression of PAR-2 mRNA in the synovium was higher in RA than in OA. Mast cell tryptase containing the unglycosylated 31-kDa subunit was the predominant form in synovial fluid. RA patients had higher amounts of this subunit in their synovial fluid than OA patients. Mast cell tryptase and PAR-2 activating peptide stimulated the proliferation of SFCs and release of IL-8 from these cells. Mast cell tryptase secretion into RA synovial fluid is higher than OA synovial fluid. Mast cell tryptase in synovial fluid stimulates the proliferation of SFCs and the release of pro-inflammatory cytokines via PAR-2, which may contribute to exacerbation of synovitis in RA.

Emerging roles of serine proteinases in tissue turnover in arthritis

“…Tryptase and chymase can further promote ECM degradation by activating proMMPs (80)(81)(82)(83)(84) and pro-uPA (85). Mast cell tryptase is important in activating PAR-2 on synovial fibroblasts and inducing proinflammatory cytokine release (86,87). Tryptase can also enhance the release of vascular endothelial growth factor from chondrocytes, although this appears to be a PAR-independent event (88).…”

“…Synovial fibroblasts, chondrocytes, macrophages, neutrophils, mast cells, T cells, and dendritic cells all express PARs, which exhibit both antiinflammatory and proinflammatory properties, although recent data point toward a detrimental role especially in the context of immune-mediated effects in arthritis (157). A study in PAR-2 Ϫ/Ϫ mice confirmed PAR-2 as a key mediator of chronic joint inflammation (158), and this is likely to be a consequence of activation by mast cell-derived tryptase (86,87). PAR-2 is associated with the perpetuation of inflammation in both RA and OA, because PAR-2 levels are elevated by proinflammatory cytokines and growth factors (159,160), while PAR-2 activation in peripheral blood monocytes and chondrocytes enhances proinflammatory cytokine production (161,162).…”

“…PAR-2 is the most consistently observed chondrocyte PAR, although differing expression profiles for the other PARs have been reported (see ref. 169 and the references therein), while synovial tissues express all except PAR-4 (86,87,170). NE and CTG inactivate (or "disarm") PAR-1 and PAR-2, while NE also inactivates PAR-3 (see ref.…”

Immune Modulation to Improve Tissue Engineering Outcomes for Cartilage Repair in the Osteoarthritic Joint

“…Elevated mast cell counts in the synovial fluid of patients with OA have been reported, with higher levels of histamine, tryptase, and nitrite detected in OA synovial fluid. 60,61 Furthermore, a role for TNF-a in the induction of mast cell chemotaxis in OA has been elucidated. 62 Studies have suggested that the observed increase of mast cells in OA may be due to the expansion of a tryptase but not chymase containing population, with an increase in this population reported in the synovial tissue of OA patients compared with control.…”

Vitamin E slows down the progression of osteoarthritis

“…Various theories on the pathology of osteoarthritis are being investigated that may lead to new therapeutic options. These relate to the role of skeletal muscle (11)(12)(13)(14), the effect of nucleic acid metabolism (15,16), sex gland functions (17)(18)(19), the action of stable mast cells (20,21) and the importance of the subchondral vascular system (9,22,23) in osteoarthritis and its progression. In the present review, the possibility that vitamin E may be able to delay the progression of osteoarthritis was explored through studying the potential role of this nutritional factor in each of these mechanisms.…”