Hyaluronic acid inhibits the expression of u-PA, PAI-1, and u-PAR in human synovial fibroblasts of osteoarthritis and rheumatoid arthritis.

OBJECTIVE

Intraarticular administration of hyaluronic acid (HA) has been widely used for the treatment of osteoarthritis (OA). Fibrinolysis is closely related to the pericellular proteolysis involved in inflammation. However, the role of HA in the regulation of fibrinolytic factors is not yet known. We investigated the effect of HA on the pericellular fibrinolytic system of human synovial fibroblasts derived from OA and rheumatoid arthritis (RA).

METHODS

Human synovial fibroblasts obtained from OA and RA were cultured in the presence and absence of HA. The antigen of urokinase-type plasminogen activator (u-PA) and plasminogen activator inhibitor-1 (PAI-1) were measured by ELISA, and u-PA activity was evaluated by electrophoretic enzymography. The binding assay of u-PA and the immunohistochemical analysis of u-PA were employed to detect u-PA receptor (u-PAR).

RESULTS

HA suppressed the secretion of both u-PA and PAI-1 antigens from the synovial fibroblasts of OA to their conditioned medium. Suppression of u-PA activity in OA synovial fibroblasts was more marked than in those of RA. The u-PA binding assay of OA and RA synovial fibroblasts revealed a single class of binding site: dissociation constant (Kd) 23.7 nM, maximal number of binding sites (Bmax) 3.11x10(4) binding sites/cell; Kd 16.5 nM, Bmax of 9.88x10(4) binding sites/cell, respectively. HA decreased Bmax in fibroblasts of both OA and RA. Immunohistochemical analysis showed that u-PAR was constitutively expressed in both synovial fibroblasts, but if these cells were treated with HA, the decrease of the staining of u-PAR was more pronounced in the cells of RA than in OA.

CONCLUSION

Pericellular fibrinolytic activity mediated by the u-PA/u-PAR system and PAI-1 was attenuated by HA in synovial fibroblasts derived from OA and RA. Thus, HA may be a useful agent to inhibit the inflammation of arthritis.