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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
YIH-SHOU HSIEH, SHUN-FA YANG, KO-HUANG LUE, SHU-CHEN CHU, TZUNG-JE LI, and KO-HSIU LU ABSTRACT. 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 1a (IL-1a) 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-1a- 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-1a 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. (First Release Feb 1 2007; J Rheumatol 2007;34:785–93) Key Indexing Terms:
PLASMINOGEN ACTIVATOR INHIBITOR From the Institute of Biochemistry and Biotechnology, Institute of Medicine, Chung Shan Medical University; Department of Orthopaedic Surgery, Chung Shan Medical University Hospital; and Department of Food Science, Central Taiwan University of Science and Technology, Taichung, Taiwan. Supported by a grant from the Research Section of Chung Shan Medical University (CSMU94-OM-B-019) and National Science Council, Taiwan (NSC93-2314-B-040-003). Y-S. Hsieh, PhD, Institute of Biochemistry and Biotechnology, Chung Shan Medical University; S-F. Yang, PhD; K-H. Lue, MD, Institute of Medicine, Chung Shan Medical University; S-C. Chu, PhD, Department of Food Science, Central Taiwan University of Science and Technology; T-J. Li, MD, Department of Orthopaedic Surgery, Chung Shan Medical University Hospital; K-H. Lu, MD, PhD, Department of Orthopaedic Surgery, Chung Shan Medical University Hospital, Institute of Medicine, Chung Shan Medical University. Address reprint requests to Dr. K-H. Lu, 110, Section 1, Chien-Kuo N. Road, Taichung 402, Taiwan. E-mail: cshy307@csh.org.tw Accepted for publication November 1, 2006.
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