Korean J Med.  2006 Aug;71(2):182-188.

Regulation of aggrecanase-1 and aggrecanase-2 expressions by hypoxia and cytokines in rheumatoid fibroblast-like synoviocytes

• Kim HJ
• Bae EK
• Kim J
• Chai JY
• Jeon CH
• Cha HS
• Ahn KS
• Koh EM

Abstract

BACKGROUND: While aggrecanases (aggrecanase-1 and aggrecanase-2) are substantially responsible for cartilage aggrecan breakdown in rheumatoid arthritis (RA), not much information is available on the regulation or expression of the two key aggrecanases in rheumatoid fibroblast-like synoviocytes (FLS). The aim of this study is to determine the effect of hypoxia and several cytokines on the expression of the aggrecanases in rheumatoid FLS.
METHODS
FLS obtained from RA patients were cultured under hypoxic condition for 24 hours. Quantitative polymerase chain reaction assays for mRNA expression of aggrecanase-1 and aggrecanase-2 were performed on FLS cultured under hypoxia. Additionally, to see the effect of various cytokines, same experiments were conducted after treating FLS with IL-1beta, IL-6, EGF, TGF-beta and TNF-alpha, compared with control.
RESULTS
Hypoxia significantly increased both aggrecanase-1 and -2 mRNA expression in rheumatoid FLS compared with normoxia. IL-1beta, IL-6, EGF, TGF-beta and TNF-alpha upregulated the mRNA expression of aggrecanase-1. Both EGF and TGF-beta upregulated the mRNA expression of aggrecanase-2, but TNF-alpha significantly downregulated the mRNA expression of aggrecanase-2.
CONCLUSIONS
These results showed upregulation of aggrecanase-1 and -2 by hypoxia and differential regulation of aggrecanase-1 and -2 by various cytokines in rheumatoid FLS. It suggests that hypoxia and cytokines enhance the aggrecanase activity of RA FLS and contribute to joint destruction.

Keyword

Hypoxia; Aggrecanase; Rheumatoid arthritis

MeSH Terms

Aggrecans
Anoxia*
Arthritis, Rheumatoid
Cartilage
Cytokines*
Epidermal Growth Factor
Humans
Interleukin-6
Joints
Polymerase Chain Reaction
RNA, Messenger
Transforming Growth Factor beta
Tumor Necrosis Factor-alpha
Up-Regulation
Aggrecans
Cytokines
Epidermal Growth Factor
Interleukin-6
RNA, Messenger
Transforming Growth Factor beta
Tumor Necrosis Factor-alpha