Myeloid-related proteins S100A8/S100A9 regulate joint inflammation and cartilage destruction during antigen-induced arthritis.
OBJECTIVE
To study the active involvement of Myeloid-related proteins S100A8 and S100A9 in joint inflammation and cartilage destruction during antigen-induced arthritis (AIA).


METHODS
Joint inflammation and cartilage destruction was measured with 99mTc uptake and histology. The role of S100A8/A9 was investigated by inducing AIA in S100A9-/- mice that also lack S100A8 at protein level, or after intra-articular injection of rS100A8 in mouse knee joints. Cartilage destruction was measured using immunolocalisation of the neoepitope VDIPEN or NITEGE. mRNA levels of matrix metalloproteinases (MMPs) and cytokines were measured using reverse transcriptase (RT)-PCR.


RESULTS
Immunisation of S100A9-/- mice with the antigen mBSA induced normal cellular and humoral responses, not different from wild type (WT) controls. However, joint swelling measured at day 3 and 7 after AIA induction was significantly lower (36 and 70%, respectively). Histologically, at day 7 AIA, cellular mass was much lower (63-80%) and proteoglycan depletion from cartilage layers was significantly reduced (between 50-95%). Cartilage destruction mediated by MMPs was absent in S100A9-/- mice but clearly present in controls. MMP3, 9 and 13 mRNA levels were significantly lowered in arthritic synovia of S100A9-/-. In vitro stimulation of macrophages by the heterodimer S100A8/A9 or S100A8 elevated mRNA levels of MMP3, 9 and in particular MMP13. Intra-articular injection of S100A8 caused prominent joint inflammation and depletion of proteoglycans at day 1. Significant upregulation of mRNA levels of S100A8/A9, cytokines (interleukin 1 (IL1)), MMPs (MMP3, MMP13 and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)4) was found in the synovium and correlated with strong upregulation of NITEGE neoepitopes within the cartilage layers.


CONCLUSIONS
S100A8/A9 regulate joint inflammation and cartilage destruction during antigen-induced arthritis.
van Lent
P L E M
PL
Department of Rheumatology, Radboud University Medical Centre, Nijmegen, Building 850, Geert Grooteplein 26-28, Nijmegen, The Netherlands. P.vanlent@reuma.umcn.nl
Grevers
L
L
Blom
A B
AB
Sloetjes
A
A
Mort
J S
JS
Vogl
T
T
Nacken
W
W
van den Berg
W B
WB
Roth
J
J
D051722:ADAM Proteins / Q000378:metabolism; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology; D040501:Calgranulin A; D040502:Calgranulin B / Q000276:immunology*; D002358:Cartilage, Articular / Q000473:pathology; D016923:Cell Death; D019902:Chondrocytes / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D007111:Immunity, Cellular; D007074:Immunoglobulin G / Q000096:biosynthesis; D017737:Macrophages, Peritoneal / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011509:Proteoglycans / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D009418:S100 Proteins / Q000276:immunology*; D012710:Serum Albumin, Bovine / Q000276:immunology; D013583:Synovial Membrane / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D040501:Calgranulin A; D040502:Calgranulin B; D016207:Cytokines; D007074:Immunoglobulin G; D011509:Proteoglycans; D012333:RNA, Messenger; D009418:S100 Proteins; C086145:S100a8 protein, mouse; C029180:methylated bovine serum albumin; D012710:Serum Albumin, Bovine; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases