Scavenger receptor class A type I/II determines matrix metalloproteinase-mediated cartilage destruction and chondrocyte death in antigen-induced arthritis.
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-1beta [IL-1beta], IL-10, and tumor necrosis factor alpha) 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-1beta 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.


CONCLUSIONS
Our findings indicate that SR-AI and SR-AII are crucial receptors involved in mediating severe cartilage destruction in AIA.
Department of Rhumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. p.vanlent@reuma.umcn.nl
P L E M
PL
van Lent
W
W
Hofkens
A B
AB
Blom
L
L
Grevers
A
A
Sloetjes
N
N
Takahashi
L J
LJ
van Tits
T
T
Vogl
J
J
Roth
M P
MP
de Winther
W B
WB
van den Berg
D000818:Animals; D000941:Antigens / Q000009:adverse effects; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D040501:Calgranulin A; D040502:Calgranulin B; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D017452:Receptors, IgG / Q000378:metabolism; D009418:S100 Proteins / Q000378:metabolism; D051117:Scavenger Receptors, Class A / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000009:adverse effects; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology
D000941:Antigens; D040501:Calgranulin A; D040502:Calgranulin B; C485701:Fcgr1 protein, mouse; D053583:Interleukin-1beta; D017452:Receptors, IgG; D009418:S100 Proteins; C086145:S100a8 protein, mouse; D051117:Scavenger Receptors, Class A; D012710:Serum Albumin, Bovine; D020782:Matrix Metalloproteinases