title: Local fibroblast proliferation but not influx is responsible for synovial hyperplasia in a murine model of rheumatoid arthritis.
abstract: Synovial fibroblasts play crucial roles in inflammation and joint destruction in rheumatoid arthritis (RA). How they accumulate in the RA joints remains unclear. This study was conducted to discern whether cellular influx from the outside of the joints and local proliferation are responsible for synovial fibroblast accumulation in an animal model of RA. We found that synovial fibroblasts were identified as GFP+ cells using collagen type I alpha 2 (Col1a2)-GFP transgenic reporter mice. Then, bone marrow transplantation and parabiosis techniques were utilized to study the cellular influx. Irradiated wild-type mice were transplanted with bone marrow from Col1a2-GFP mice. Col1a2-GFP and wild-type mice were conjoined for parabiosis. The transplanted mice and the parabionts were subjected to collagen antibody-induced arthritis (CAIA). We found no GFP+ cells in the hyperplastic synovial tissues from the transplanted mice with CAIA and from the wild-type parabionts with CAIA. Furthermore, normal and CAIA synovial tissues from Col1a2-GFP mice and from fluorescent ubiquitination-based cell cycle indicator (Fucci) transgenic mice, in which cells in S/G2/M phases of the cell cycle express Azami-Green, were studied for Ki67, a cellular proliferation marker, and vimentin, a fibroblast marker, expression. The percentages of Ki67+/GFP+ and Azami-Green+/vimentin+ cells in the CAIA synovial tissues were higher than those in the untreated synovial tissues (34% vs. 0.40% and 19% vs. 0.26%, respectively). These findings indicate that local fibroblast proliferation but not cellular influx is responsible for the synovial hyperplasia in CAIA. Suppression of proliferation of the local synovial fibroblasts should be a promising treatment for RA.
authors.affiliation: Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan; Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST) Program, Sanbancho, Chiyoda-ku, Tokyo, 102-0075, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Matsuo
authors.affiliation: Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan; Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST) Program, Sanbancho, Chiyoda-ku, Tokyo, 102-0075, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Mizoguchi
authors.affiliation: Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan; Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST) Program, Sanbancho, Chiyoda-ku, Tokyo, 102-0075, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Kimito
authors.initials: K
authors.lastname: Kawahata
authors.affiliation: Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST) Program, Sanbancho, Chiyoda-ku, Tokyo, 102-0075, Japan; Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueha
authors.affiliation: Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST) Program, Sanbancho, Chiyoda-ku, Tokyo, 102-0075, Japan; Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
authors.affiliation: Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST) Program, Sanbancho, Chiyoda-ku, Tokyo, 102-0075, Japan; Center for Matrix Biology and Medicine, Graduate School of Medicine and the Institute of Medical Sciences, Tokai University, 143 Shimo-kasuya, Isehara, Kanagawa, 259-1193, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Inagaki
authors.affiliation: Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Miyasaka
authors.affiliation: Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan; Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST) Program, Sanbancho, Chiyoda-ku, Tokyo, 102-0075, Japan. Electronic address: kohsaka.rheu@tmd.ac.jp.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kohsaka
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology*; D002465:Cell Movement / Q000276:immunology; D049109:Cell Proliferation; D005347:Fibroblasts / Q000276:immunology / Q000473:pathology*; D006965:Hyperplasia / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D013583:Synovial Membrane / Q000276:immunology / Q000473:pathology*
keywords: Cellular influx; Cellular proliferation; Collagen antibody-induced arthritis; Rheumatoid arthritis; Synovial fibroblast; Synovial hyperplasia