TY - JOUR T1 - Upregulation of urokinase-type plasminogen activator and inhibitor and gelatinase expression via 3 mitogen-activated protein kinases and PI3K pathways during the early development of osteoarthritis. JF - The Journal of Rheumatology JO - J Rheumatol SP - 785 LP - 793 VL - 34 IS - 4 AU - Yih-Shou Hsieh AU - Shun-Fa Yang AU - Ko-Huang Lue AU - Shu-Chen Chu AU - Tzung-Je Li AU - Ko-Hsiu Lu Y1 - 2007/04/01 UR - http://www.jrheum.org/content/34/4/785.abstract N2 - OBJECTIVE: To examine whether upregulation of urokinase-type plasminogen activator (u-PA), PA inhibitor-1 (PAI-1), and gelatinases [matrix metalloproteinase (MMP)-2 and MMP-9] in early knee osteoarthritis (OA) of humans occurs through 3 major mitogen-activated protein kinases (MAPK): extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 kinase signaling pathways, and the phosphatidylinositol 3-kinase (PI3K) signaling pathway. METHODS: Enzyme linked immunosorbent assay and gelatin zymography were used to investigate the effects of ERK 1/2 inhibitor U0126, JNK and p38 inhibitor SB203580, and PI3K inhibitor LY294002 on the secretion of u-PA, PAI-1, MMP-2, and MMP-9 in early osteoarthritic tissue cultures, with or without interleukin 1alpha (IL-1alpha) and lipopolysaccharide (LPS) induction. RESULTS: Our findings were: (1) latent and active forms of MMP-9 secretion in synovial and some meniscal cultures were inhibited significantly by U0126, SB203580, and LY294002; (2) latent and active forms of MMP-2 secretion were also inhibited significantly by U0126 and LY294002, but not by SB203580, except for active MMP-2 in synovial cultures; (3) a similar observation was seen in IL-1alpha- and LPS-treated cultures; and (4) U0126, SB203580, and LY294002 significantly decreased u-PA and PAI-1 levels in all cultures in the presence or absence of IL-1alpha and LPS. CONCLUSION: MAPK ERK, JNK, and p38 signaling pathways and the PI3K signaling pathway are involved in upregulation of u-PA, PAI-1, and gelatinase expression during early development of knee OA. Thus, blocking PA/plasmin and gelatinase expression by novel physiologic and pharmacological inhibitors could be an important therapeutic or preventive approach for early OA. ER -