title: C5orf30 is a negative regulator of tissue damage in rheumatoid arthritis.
abstract: The variant rs26232, in the first intron of the chromosome 5 open reading frame 30 (C5orf30) locus, has recently been associated with both risk of developing rheumatoid arthritis (RA) and severity of tissue damage. The biological activities of human C5orf30 are unknown, and neither the gene nor protein show significant homology to any other characterized human sequences. The C5orf30 gene is present only in vertebrate genomes with a high degree of conservation, implying a central function in these organisms. Here, we report that C5orf30 is highly expressed in the synovium of RA patients compared with control synovial tissue, and that it is predominately expressed by synovial fibroblast (RASF) and macrophages in the lining and sublining layer of the tissue. These cells play a central role in the initiation and perpetuation of RA and are implicated in cartilage destruction. RASFs lacking C5orf30 exhibit increased cell migration and invasion in vitro, and gene profiling following C5orf30 inhibition confirmed up-regulation of genes involved in cell migration, adhesion, angiogenesis, and immune and inflammatory pathways. Importantly, loss of C5orf30 contributes to the pathology of inflammatory arthritis in vivo, because inhibition of C5orf30 in the collagen-induced arthritis model markedly accentuated joint inflammation and tissue damage. Our study reveal C5orf30 to be a previously unidentified negative regulator of tissue damage in RA, and this protein may act by modulating the autoaggressive phenotype that is characteristic of RASFs.
authors: Academic Unit of Rheumatology, University of Sheffield, Sheffield S10 2RX, United Kingdom; m.muthana@shef.ac.uk.
authors: Munitta
authors: M
authors: Muthana
authors: Academic Unit of Rheumatology, University of Sheffield, Sheffield S10 2RX, United Kingdom;
authors: Sarah
authors: S
authors: Hawtree
authors: Academic Unit of Rheumatology, University of Sheffield, Sheffield S10 2RX, United Kingdom;
authors: Adam
authors: A
authors: Wilshaw
authors: Department of Rheumatology, Dublin Academic Medical Centre and the Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin D04 W6F6, Ireland;
authors: Eimear
authors: E
authors: Linehan
authors: Academic Unit of Rheumatology, University of Sheffield, Sheffield S10 2RX, United Kingdom;
authors: Hannah
authors: H
authors: Roberts
authors: Academic Unit of Rheumatology, University of Sheffield, Sheffield S10 2RX, United Kingdom;
authors: Sachin
authors: S
authors: Khetan
authors: Academic Unit of Rheumatology, University of Sheffield, Sheffield S10 2RX, United Kingdom;
authors: Gbadebo
authors: G
authors: Adeleke
authors: Academic Unit of Rheumatology, University of Sheffield, Sheffield S10 2RX, United Kingdom;
authors: Fiona
authors: F
authors: Wright
authors: Academic Unit of Rheumatology, University of Sheffield, Sheffield S10 2RX, United Kingdom;
authors: Mohammed
authors: M
authors: Akil
authors: Department of Rheumatology, Dublin Academic Medical Centre and the Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin D04 W6F6, Ireland;
authors: Ursula
authors: U
authors: Fearon
authors: Department of Rheumatology, Dublin Academic Medical Centre and the Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin D04 W6F6, Ireland;
authors: Douglas
authors: D
authors: Veale
authors: Centre for Membrane Interactions and Dynamics, and Krebs Institute, Department of Chemistry, University of Sheffield, Sheffield S3 7HF, United Kingdom.
authors: Barbara
authors: B
authors: Ciani
authors: Academic Unit of Rheumatology, University of Sheffield, Sheffield S10 2RX, United Kingdom; Department of Rheumatology, Dublin Academic Medical Centre and the Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin D04 W6F6, Ireland;
authors: Anthony G
authors: AG
authors: Wilson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002356:Cartilage / Q000473:pathology; D002470:Cell Survival; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007596:Joints / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010802:Phylogeny; D034741:RNA, Small Interfering / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013583:Synovial Membrane / Q000378:metabolism*; D014018:Tissue Distribution; D014945:Wound Healing; D055114:X-Ray Microtomography
chemical_list: C000603955:C5orf30 protein, mouse; D002352:Carrier Proteins; C586223:MACIR protein, human; D010750:Phosphoproteins; D034741:RNA, Small Interfering
keywords: fibroblast; genetics; inflammation; rheumatoid arthritis; tissue damage