title: Effect of Tumor Necrosis Factor Inhibitor Therapy on Osteoclasts Precursors in Rheumatoid Arthritis.
abstract: Objective. Tumor necrosis factor (TNF) increases circulating osteoclast (OC) precursors numbers by promoting their proliferation and differentiation. The aim of this study was to assess the effect of TNF inhibitors (TNFi) on the differentiation and activity of OC in rheumatoid arthritis (RA) patients.Methods.Seventeen RA patients treated with TNFi were analyzed at baseline and after a minimum follow-up period of 6 months. Blood samples were collected to assess receptor activator of nuclear factor kappa-B ligand (RANKL) surface expression on circulating leukocytes and frequency and phenotype of monocyte subpopulations. Quantification of serum levels of bone turnover markers, in vitro OC differentiation assays, and qRT-PCR for OC specific genes was performed.Results. After TNFi therapy, patients had reduced RANKL surface expression in B-lymphocytes and the frequency of circulating classical CD14brightCD16-monocytes was decreased. Serum levels of sRANKL, sRANKL/OPG ratio, and CTX-I were reduced in RA patients after TNFi treatment. Moreover, after exposure to TNFi, osteoclast differentiation and activity were decreased, as well as the expression of TRAF6 and cathepsin K.Conclusion. We propose that TNFi arrests bone loss and erosion, through two pathways: direct reduction of osteoclast precursor numbers and inhibition of intracellular signaling pathways acting through TRAF6.
authors.affiliation: Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Inês P
authors.identifier: 0000-0001-7671-2539
authors.initials: IP
authors.lastname: Perpétuo
authors.affiliation: Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Joana
authors.identifier: 0000-0003-0310-4641
authors.initials: J
authors.lastname: Caetano-Lopes
authors.affiliation: Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Rodrigues
authors.affiliation: Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Rheumatology Department, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, EPE, Lisbon Academic Medical Centre, Lisboa, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Campanilho-Marques
authors.affiliation: Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Rheumatology Department, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, EPE, Lisbon Academic Medical Centre, Lisboa, Portugal.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ponte
authors.affiliation: EpiDoC Unit, CEDOC, NOVA Medical School, Universidade Nova de Lisboa, Lisboa, Portugal.
authors.forename: Helena
authors.initials: H
authors.lastname: Canhão
authors.affiliation: Musculoskeletal Diseases and Inflammation Research Group, Biomedicum Helsinki 1, Faculty of Medicine, Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Mari
authors.initials: M
authors.lastname: Ainola
authors.affiliation: Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Rheumatology Department, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, EPE, Lisbon Academic Medical Centre, Lisboa, Portugal.
authors.forename: João E
authors.identifier: 0000-0003-1432-3671
authors.initials: JE
authors.lastname: Fonseca
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D056657:Cathepsin K / Q000096:biosynthesis; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D055017:Monocyte-Macrophage Precursor Cells / Q000378:metabolism / Q000473:pathology; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D053245:RANK Ligand / Q000096:biosynthesis; D048029:TNF Receptor-Associated Factor 6 / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D053245:RANK Ligand; D048029:TNF Receptor-Associated Factor 6; C439524:TNF protein, human; C505688:TNFSF11 protein, human; C000604754:Tifab protein, human; D014409:Tumor Necrosis Factor-alpha; C534130:CTSK protein, human; D056657:Cathepsin K