Down-regulation of survivin alleviates experimental arthritis.
Survivin is a proto-oncogene that regulates cell division and apoptosis. It is a molecular marker of cancer. Recently, survivin has emerged as a feature of RA, associated with severe joint damage and poor treatment response. The present study examined if inhibition of survivin affects experimental arthritis, which was induced in mBSA-immunized mice by an injection of mBSA in the knee joint or developed spontaneously in collagen type II-immunized mice. The inhibition of survivin transcription by a lentivirus shRNA construct alleviated joint inflammation and reduced bone damage. The inhibition of survivin reduced the levels of metalloproteinases, β-catenin, and vimentin, limiting the invasive capacity of synovia, while no inhibition of osteoclastogenesis could be found. The inhibition of survivin led to a p53-independent reduction of T cell proliferation and favored the transcription and activity of Blimp-1, which limited IL-2 production and facilitated formation of regulatory Foxp3(+)CD4(+) and effector CD8(+) T cells. The study shows that the inhibition of survivin is sufficient to reduce joint inflammation and bone damage in preclinical models of arthritis. Antiarthritic effects of survivin inhibition are related to p53-independent control of lymphocyte proliferation.
Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, University of Gothenburg, Sweden.
K M E
KM
Andersson
Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, University of Gothenburg, Sweden.
M N D
MN
Svensson
Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, University of Gothenburg, Sweden.
M C
MC
Erlandsson
Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, University of Gothenburg, Sweden.
I-M
IM
Jonsson
Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, University of Gothenburg, Sweden maria.bokarewa@rheuma.gu.se.
M I
MI
Bokarewa
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D012097:Repressor Proteins / Q000096:biosynthesis / Q000276:immunology*; D000077022:Survivin
C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D012097:Repressor Proteins; D000077022:Survivin
Blimp-1; T cells; Treg; erosions; p53; synovitis