title: Anti IL-17A therapy inhibits bone loss in TNF-α-mediated murine arthritis by modulation of the T-cell balance.
abstract: Tumour necrosis factor alpha (TNF-α) is a major inducer for inflammation and bone loss. Here, we investigated whether interleukin (IL)-17 plays a role in TNF-α-mediated inflammation and bone resorption. Human TNF-α transgenic (hTNFtg) mice were treated with a neutralizing anti-IL-17A antibody and assessed for inflammation, cartilage and bone damage. T-cell transcription factors and lymphokine patterns were measured in the LNs. IL-17A inhibition in the absence of IL-1 was also evaluated by treating hTNFtg/IL-1(-/-)  mice with an IL-17A neutralizing antibody. IL-17A neutralization had only minor effects on TNF-α-induced inflammation but effectively reduced local and systemic bone loss by blocking osteoclast differentiation in vivo. Effects were based on a shift to bone-protective T-cell responses such as enhanced Th2 differentiation, IL-4 and IL-12 expression and Treg cell numbers. Whereas inflammation in hTNFtg/IL-1(-/-)  mice was highly sensitive to IL-17A blockade, no shift in the T-cell lineages and no additional benefit on bone mass were observed in response to IL-17A neutralization. We thus conclude that IL-17A is a key mediator of TNF-α-induced bone loss by closely interacting with IL-1 in blocking bone protective T-cell responses.
authors.affiliation: Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Zwerina
authors.forename: Marije
authors.initials: M
authors.lastname: Koenders
authors.forename: Axel
authors.initials: A
authors.lastname: Hueber
authors.forename: Renoud J
authors.initials: RJ
authors.lastname: Marijnissen
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baum
authors.forename: Gisela Ruiz
authors.initials: GR
authors.lastname: Heiland
authors.forename: Mario
authors.initials: M
authors.lastname: Zaiss
authors.forename: Iain
authors.initials: I
authors.lastname: McLnnes
authors.forename: Leo
authors.initials: L
authors.lastname: Joosten
authors.forename: Wim
authors.initials: W
authors.lastname: van den Berg
authors.forename: Jochen
authors.initials: J
authors.lastname: Zwerina
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology / Q000628:therapy*; D001862:Bone Resorption; D002478:Cells, Cultured; D006801:Humans; D007167:Immunotherapy; D007249:Inflammation; D007375:Interleukin-1 / Q000235:genetics; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D058408:Th1-Th2 Balance; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage
chemical_list: D000911:Antibodies, Monoclonal; D007375:Interleukin-1; D020381:Interleukin-17; D014409:Tumor Necrosis Factor-alpha