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Regulation of plasminogen activator inhibitor 1 expression in human osteoarthritic chondrocytes by fluid shear stress: Role of protein kinase C-alpha
Arthritis & Rheumatism, 08/05/09

Yeh CC et al. – OA chondrocytes from lesional sites and those from nonlesional sites of human cartilage have differential responses to shear stress with regard to PAI–1 gene expression, and therefore diverse functional consequences can be observed.

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Chih-Chang,Yeh MD, 08/06/09

Biochemical and genetic factors, as well as mechanical stress, contribute to the OA lesion in human cartilage by disrupting chondrocyte–matrix ssociations and altering metabolic responses in the chondrocyte.Plasmin is involved in various physiologic mechanisms, including thrombolysis, cell migration, metastasis, and arthritis formation. In addition, plasmin can activate metalloproteinases and plays an important role in modulating cartilage function . Urokinase plasminogen activator (uPA), tissue-type plasminogen activator(tPA), and their inhibitor, plasminogen activator inhibitor-1 (PAI-1), are present in the cartilage to modulate plasmin activation and the degradation of ECM. OA cartilage has been shown to display increased plasmin activity and elevated levels of uPA and tPA, as well as a decrease in PAI-1 expression. Chondrocytes show different responses to distinct levels of mechanical stress. Previous studies indicated that 5–10 dyn/cm2 shear stress has anticatabolic effects on articular cartilage, and that shear stresses higher than 16 dyn/cm2 can induce chondrocyte apoptosis,inflammation, and cartilage degradation . In our study, we assessed SW-1353 chondrocytes in a fluid flow chamber to investigate the effect of shear stress on the signaling pathway leading to PAI-1 gene expression.In this system, shear stresses of 5 dyn/cm2 and 10dyn/cm2 were found to activate the PKC signal transduction pathway, followed by an increase in PAI-1 promoter activity through regulation of Sp-1 DNA binding,and these events led to increased PAI-1 expression on chondrocytes. Interestingly, the present study characterized a novel mechanism in which moderate levels of shear stress play an important role in the regulation of PAI-1 expression in normal human chondrocytes, but this regulatory response is deficient in human OA chondrocytes at sites of lesions. Thus, in normal chondrocytes and in OA chondrocytes from nonlesional sites,shear stress at 10 dyn/cm2 induces the up-regulation of PAI-1 expression via activation of the PKC and Sp-1 signaling pathways. In contrast, human OA articular chondrocytes from lesional sites not only have significantly lower PAI-1expression under static conditions but also do not possess the ability to respond to moderate shear stresses to increase PAI-1 expression. The abnormal response of lesion-derived OA chondrocytes to excessive loading is a likely contributor to the dysregulation of chondrocyte function, favoring disequilibrium between the catabolic and anabolic activities of the chondrocyte in remodeling the cartilage ECM by the production of metalloproteinases and aggrecanase. The progressive degradation of the cartilage matrix that occurs in OA indicates that there is a local imbalance in the proteinase–inhibitor content.

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