Scavenger receptor class A type I/II determines matrix metalloproteinase–mediated cartilage destruction and chondrocyte death in antigen-induced arthritis
✍ Scribed by P. L. E. M. van Lent; W. Hofkens; A. B. Blom; L. Grevers; A. Sloetjes; N. Takahashi; L. J. van Tits; T. Vogl; J. Roth; M. P. de Winther; W. B. van den Berg
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- English
- Weight
- 314 KB
- Volume
- 60
- Category
- Article
- ISSN
- 0004-3591
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✦ Synopsis
Abstract
Objective
Scavenger receptor class A type I (SR‐AI) and SR‐AII are expressed by macrophages in particular and bind and internalize a broad range of molecules (including endotoxins, apoptotic bodies, and oxidized low‐density lipoprotein). This study was undertaken to investigate the role of SR‐AI/II in mediating severe cartilage destruction in antigen‐induced arthritis (AIA).
Methods
AIA was induced in the knee joints of SR‐AI/II^−/−^ mice and wild‐type (WT) controls. Joint inflammation and cartilage destruction (chondrocyte death) were measured by examining the histology of total knee joints. Matrix metalloproteinase (MMP)–mediated neoepitopes were measured by immunolocalization using anti‐VDIPEN antibodies and chondrocyte activation with anti‐S100A8 antibodies. Messenger RNA (mRNA) levels were determined in inflamed synovium using microarray analysis and quantitative reverse transcriptase–polymerase chain reaction. In synovial washouts, cytokines (interleukin‐1β [IL‐1β], IL‐10, and tumor necrosis factor α) and S100A8/S100A9 were measured using Luminex and enzyme‐linked immunosorbent assay.
Results
Levels of SR‐AI/II mRNA were strongly elevated in inflamed synovium in AIA. On days 2, 8, and 14 after AIA induction, joint inflammation (exudates/infiltrate) was similar between the 2 groups. In WT mice, severe cartilage destruction was found in multiple cartilage surfaces of the inflamed knee joint on day 14 after AIA induction. MMP‐mediated matrix destruction ranged between 40% and 60%, and chondrocyte death was prominent in 40–75% of the cartilage surfaces. In striking contrast, in SR‐AI/II^−/−^ mice, despite comparable joint inflammation, pronounced cartilage destruction was almost completely absent. Levels of IL‐1β and S100A8/S100A9 were significantly lower on days 7 and 14 after AIA induction, but levels of mRNA for various MMPs (MMP‐2, MMP‐3, MMP‐9, and MMP‐13) were comparable.
Conclusion
Our findings indicate that SR‐AI and SR‐AII are crucial receptors involved in mediating severe cartilage destruction in AIA.