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.
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.


CONCLUSIONS
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.
Hsieh
Yih-Shou
YS
Institute of Biochemistry and Biotechnology, Shan Medical University.
Yang
Shun-Fa
SF
Lue
Ko-Huang
KH
Chu
Shu-Chen
SC
Li
Tzung-Je
TJ
Lu
Ko-Hsiu
KH
D018929:Cell Culture Techniques; D051445:Fibrocartilage / Q000201:enzymology / Q000503:physiopathology; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008592:Menisci, Tibial / Q000201:enzymology / Q000503:physiopathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D020370:Osteoarthritis, Knee / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013583:Synovial Membrane / Q000201:enzymology / Q000503:physiopathology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D017395:Plasminogen Activator Inhibitor 1; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9