title: A betulinic acid derivative SH479 inhibits collagen-induced arthritis by modulating T cell differentiation and cytokine balance.
abstract: The ideal therapeutic drug for rheumatoid arthritis (RA) should not only inhibit inflammation, but also prevent articular joint damage and particularly inhibit osteoclastogenesis. Betulinic acid (BA) is a natural pentacyclic triterpene that has displayed moderate anti-inflammatory and anti-osteoclastogenesis activities in various experimental systems, suggesting that BA or its derivatives could have an inhibitory effect on RA. In this study, we screened BA derivatives and found a heterocyclic ring-fused BA derivative, SH479, which had greater inhibitory effect than BA on Th17 differentiation. Moreover, we investigated the immune regulatory activity and potential therapeutic effects of SH479 in an experimental model of rheumatoid arthritis, the collagen-induced arthritis (CIA) mouse model. SH479 significantly inhibited Th1 and Th17 polarization, antigen-specific T cell proliferation and splenic lymphocyte-induced osteoclastogenesis. Furthermore, it diminished arthritis scores as well as bone destruction and cartilage depletion in the CIA mouse model. The protective effect of SH479 was accompanied by decreased levels of pro-inflammatory cytokines IL-17 and IFN-γ, together with enhanced anti-inflammatory cytokine expression including IL-10 and IL-4, as well as elevated CD4+Foxp3+cell number. At the molecular level, our results indicated that SH479 alleviated CIA through regulation of CD4+T cell subtypes by JAK-STAT pathways. In conclusion, this study demonstrates that SH479 has therapeutic potential for rheumatoid arthritis through an anti-inflammatory effect by shifting a pathogenic Th17/Th1 response to a Th2/Treg phenotype, and also through an additional articular bone protection effect.
authors.affiliation: Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China; Department of Orthopaedics, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China.
authors.forename: Shijie
authors.initials: S
authors.lastname: Chen
authors.affiliation: Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Kunhang
authors.initials: K
authors.lastname: Jia
authors.affiliation: Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Bei
authors.initials: B
authors.lastname: He
authors.affiliation: Department of Chemistry, School of Chemistry and Molecular Engineering, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Qiu
authors.affiliation: Laboratory of Receptor-Based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Changsheng
authors.initials: C
authors.lastname: Du
authors.affiliation: Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, TX, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Siwko
authors.affiliation: Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China. Electronic address: hqchen@bio.ecnu.edu.cn.
authors.forename: Huaqing
authors.initials: H
authors.lastname: Chen
authors.affiliation: Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China; Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, TX, USA. Electronic address: myliu@bio.ecnu.edu.cn.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.affiliation: Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China. Electronic address: jluo@bio.ecnu.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Luo
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000737:chemistry / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation; D049109:Cell Proliferation; D016207:Cytokines / Q000097:blood*; D008297:Male; D008811:Mice, Inbred DBA; D010012:Osteogenesis; D053978:Pentacyclic Triterpenes; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D000094062:Betulinic Acid
chemical_list: D000893:Anti-Inflammatory Agents; D018501:Antirheumatic Agents; D016207:Cytokines; D053978:Pentacyclic Triterpenes; C000618011:SH479 compound; D014315:Triterpenes; D000094062:Betulinic Acid
keywords: Betulinic acid; Collagen-induced arthritis; SH479; STAT3 signaling; Th17 cell differentiation