Downregulation of rheumatoid arthritis-related antigen RA-A47 (HSP47/colligin-2) in chondrocytic cell lines induces apoptosis and cell-surface expression of RA-A47 in association with CD9

Takako Hattori, Klaus Von Der Mark, Harumi Kawaki, Yasutaka Yutani, Satoshi Kubota, Tohru Nakanishi, Heidi Eberspaecher, Benoit De Crombrugghe, Masaharu Takigawa

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Previously, we showed that gene expression of the rheumatoid arthritis-related antigen RA-A47, which is identical to human heat shock protein (HSP)47, was downregulated in chondrocytes by inflammatory cytokines such as TNFα. Associated with this phenomenon, RA-A47 appeared on the cell surface concomitant with upregulation of metabolic factors related to cartilage destruction. The upregulation of the metabolic factors could be achieved by downregulation of RA-A47 expression with ra-a47-specific anti-sense oligonucleotide. Here, we show that the enhanced surface expression of RA-A47 on a chondrocytic cell line, HCS-2/ 8 was also a direct result of RA-A47 downregulation by ra-a47 anti-sense oligonucleotide, independent of the cytokine effects. Moreover, cell-surface expression of CD9, a β1 integrin-associated transmembrane protein that is involved in cell adhesion and cell motility events, was enhanced in the ra-a47 anti-sense oligonucleotide- treated cells. The CD9 was colocalized with RA-A47 on the cell surface, where it may have affected integrin signaling. Furthermore, Annexin-V binding to the cell surface and the level of a number of apoptosis-related genes including caspase-9 were increased after ra-a47 anti-sense oligonucleotide treatment, suggesting that enhanced surface expression of RA-A47 and CD9 may be initiating apoptosis. Differential screening using a cDNA gene array showed induction of metallothionein-III and chemokine receptor CXCR4 and of factors of the Notch signaling pathway by the anti-sense treatment, but not by TNFα. Thus, here we show for the first time an alternative mechanism of inducing apoptosis by downregulating molecular chaperones, independent of the action of TNFα. The surface-exposed RA-A47 may induce autoantibodies and inflammatory reactions in autoimmune disease situations such as rheumatoid arthritis.

Original languageEnglish
Pages (from-to)191-204
Number of pages14
JournalJournal of cellular physiology
Volume202
Issue number1
DOIs
Publication statusPublished - Jan 2005

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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