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Regulation of tumor necrosis factor-alpha and tumor necrosis factor converting enzyme in human osteoarthritis
1Department of Rheumatology, Hospital for Joint Diseases, New York, USA.
Abstract:
A snake venom-like protease isolated by a differential display screen between normal and osteoarthritis (OA)-affected cartilage (designated as cSVP) has a cDNA sequence identical to tumor necrosis factor (TNF)alpha convertase enzyme (TACE) and belongs to the adamalysin group of proteases. It has unique structural properties and when expressed in baculovirus, cleaves preferentially proTNFalpha to TNFalpha. The OA-affected cartilage has upregulated mRNA for TNFalpha and TACE as compared to normal cartilage. TNFalpha and TACE regulate inflammatory mediators in OA-affected cartilage which can be inhibited by both soluble TNFalpha receptors and inhibitors of TACE. These experiments demonstrate a functional paracrine/autocrine role of TNFalpha in OA-affected cartilage that is modulated by upregulated levels of chondrocyte-derived TACE.
Insights
Osteoarthritis cartilage has increased levels of tumor necrosis factor-alpha convertase enzyme (TACE), which promotes inflammation. Inhibiting TACE or using TNF-alpha blockers can reduce inflammatory mediators in osteoarthritis.
Area of Science:
- Biochemistry
- Molecular Biology
- Rheumatology
Background:
- Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage breakdown and inflammation.
- Tumor necrosis factor-alpha (TNF-alpha) plays a significant role in OA pathogenesis by regulating inflammatory mediators.
- The enzyme responsible for processing TNF-alpha, known as TNF-alpha convertase enzyme (TACE), is implicated in OA.
Purpose of the Study:
- To identify and characterize novel proteases involved in osteoarthritis.
- To investigate the role of TACE in the inflammatory processes within OA cartilage.
- To explore potential therapeutic targets for managing OA inflammation.
Main Methods:
- Differential display screening to identify cartilage-specific proteases.
- cDNA sequencing and expression in baculovirus for protease characterization.
- Quantitative analysis of mRNA levels for TNF-alpha and TACE in normal versus OA cartilage.
- Assessment of the effects of TACE inhibition and soluble TNF-alpha receptors on inflammatory mediators.
Main Results:
- A snake venom-like protease (cSVP), identified as TACE, was isolated from OA cartilage.
- Expressed cSVP/TACE preferentially cleaved pro-TNF-alpha to TNF-alpha.
- OA cartilage exhibited upregulated mRNA expression for both TNF-alpha and TACE compared to normal cartilage.
- TNF-alpha and TACE were found to regulate inflammatory mediators in OA cartilage.
Conclusions:
- Chondrocyte-derived TACE plays a functional paracrine/autocrine role in mediating inflammation in osteoarthritis.
- Upregulated TACE levels contribute to the inflammatory environment in OA cartilage.
- Inhibitors of TACE and soluble TNF-alpha receptors show potential for therapeutic intervention in OA.