title: N-acetyl-l-cysteine controls osteoclastogenesis through regulating Th17 differentiation and RANKL production in rheumatoid arthritis.
abstract: This study aimed to determine the regulatory role of N-acetyl-l-cysteine (NAC), an antioxidant, in interleukin 17 (IL-17)-induced osteoclast differentiation in rheumatoid arthritis (RA).
  
  
  
  After RA synovial fibroblasts were stimulated by IL-17, the expression and production of receptor activator of nuclear factor κ-B ligand (RANKL) was determined by real-time polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA). Osteoclastogenesis was also determined after co-cultures of IL-17-stimulated RA synovial fibroblasts, Th17 cells and various concentrations of NAC with monocytes. After human peripheral CD4+ T cells were cultured with NAC under Th17 condition, IL-17, interferon γ, IL-4, Foxp3, RANKL, and IL-2 expression and production was determined by flow cytometry or ELISA.
  
  
  
  When RA synovial fibroblasts were stimulated by IL-17, IL-17 stimulated the production of RANKL, and NAC reduced the IL-17-induced RANKL production in a dose-dependent manner. NAC decreased IL-17-activated phosphorylation of mammalian target of rapamycin, c-Jun N-terminal kinase, and inhibitor of κB. When human peripheral blood CD14+ monocytes were cultured with macrophage colony-stimulating factor and IL-17 or RANKL, osteoclasts were differentiated, and NAC reduced the osteoclastogenesis. After human peripheral CD4+ T cells were co-cultured with IL-17-pretreated RA synovial fibroblasts or Th17 cells, NAC reduced their osteoclastogenesis. Under Th17 polarizing condition, NAC decreased Th17 cell differentiation and IL-17 and RANKL production.
  
  
  
  NAC inhibits the IL-17-induced RANKL production in RA synovial fibroblasts and IL-17-induced osteoclast differentiation. NAC also reduced Th17 polarization. NAC could be a supplementary therapeutic option for inflammatory and bony destructive processes in RA.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea.
authors.forename: Hae-Rim
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Convergent Research Consortium for Immunologic Disease, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
authors.forename: Kyoung-Woon
authors.initials: KW
authors.lastname: Kim
authors.affiliation: Convergent Research Consortium for Immunologic Disease, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
authors.forename: Bo-Mi
authors.initials: BM
authors.lastname: Kim
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea.
authors.forename: Kyung-Ann
authors.initials: KA
authors.lastname: Lee
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea.
authors.forename: Sang-Heon
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D020381:Interleukin-17 / Q000378:metabolism; D008875:Middle Aged; D010012:Osteogenesis / Q000187:drug effects* / Q000276:immunology; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013583:Synovial Membrane / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology
chemical_list: D020381:Interleukin-17; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D000111:Acetylcysteine
keywords: Acetylcysteine; Arthritis, rheumatoid; Interleukin-17; Osteogenesis; RANK ligand