Elucidation of intracellular signaling pathways in shear-activated chondrocytes: A role in arthritis

Zachary R. Healy, Norman Lee, Paul Talalay, Thomas Kensler, Konstantinos Konstantopoulos

Research output: Contribution to conferencePaper

Abstract

COX-2 expression, inflammation and apoptosis preferentially occur in areas of cartilage exposed to prolong periods of high laminar shear flow (20 dyn/cm2,48 hrs). Recent evidence has linked COX-2 inhibitors to an increased likelihood of cardiovascular anomalies, thus demanding alternative therapeutics for inflammatory diseases. Using cDNA microarray technology coupled with novel bioinformatics tools, we have identified a target set of genes repressed during extended shear loading including several Phase II genes, which contain an antioxidant-response element (ARE) in their promoter region and function to protect cells against oxidant stress. Promoter activity assays indicate both a time- and shear stress-dependent decrease in ARE promoter activity in chondrocytic cells, signifying a potential mechanism for the observed increase of reactive oxygen radicals present in osteoarthritic tissue. The use of Phase II inducers sulforaphane (1.25 μM) and D3T (5 μM) are capable of restoring phase II enzyme activity and inhibiting COX-2 transcription and PGE2 production, while also abrogating apoptosis in sheared chondrocytes. Additionally, CAY 10404, a specific COX-2 inhibitor, was able to restore Phase II activity levels and abrogate inflammatory signaling, indicating potential feedback between pro- and anti-inflammatory pathways. Phase II inducers represent a novel therapeutic tool for arthritis, lacking the potentially harmful side-effects associated with COX-2 inhibitors, while conveying many atheroprotective effects to the vascular wall, making such therapeutics extremely attractive.

Original languageEnglish (US)
Number of pages1
StatePublished - Dec 1 2005
Event05AIChE: 2005 AIChE Annual Meeting and Fall Showcase - Cincinnati, OH, United States
Duration: Oct 30 2005Nov 4 2005

Other

Other05AIChE: 2005 AIChE Annual Meeting and Fall Showcase
CountryUnited States
CityCincinnati, OH
Period10/30/0511/4/05

ASJC Scopus subject areas

  • Engineering(all)

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    Healy, Z. R., Lee, N., Talalay, P., Kensler, T., & Konstantopoulos, K. (2005). Elucidation of intracellular signaling pathways in shear-activated chondrocytes: A role in arthritis. Paper presented at 05AIChE: 2005 AIChE Annual Meeting and Fall Showcase, Cincinnati, OH, United States.