title: IL-17 promotes bone erosion in murine collagen-induced arthritis through loss of the receptor activator of NF-kappa B ligand/osteoprotegerin balance.
abstract: IL-17 is a T cell-derived proinflammatory cytokine in experimental arthritis and is a stimulator of osteoclastogenesis in vitro. In this study, we report the effects of IL-17 overexpression (AdIL-17) in the knee joint of type II collagen-immunized mice on bone erosion and synovial receptor activator of NF-kappa B ligand (RANKL)/receptor activator of NF-kappa B/osteoprotegerin (OPG) expression. Local IL-17 promoted osteoclastic bone destruction, which was accompanied with marked tartrate-resistant acid phosphatase activity at sites of bone erosion in cortical, subchondral, and trabecular bone. Accelerated expression of RANKL and its receptor, receptor activator of NF-kappa B, was found in the synovial infiltrate and at sites of focal bone erosion, using specific immunohistochemistry. Interestingly, AdIL-17 not only enhanced RANKL expression but also strongly up-regulated the RANKL/OPG ratio in the synovium. Comparison of arthritic mice from the AdIL-17 collagen-induced arthritis group with full-blown collagen-arthritic mice having similar clinical scores for joint inflammation revealed lower RANKL/OPG ratio and tartrate-resistant acid phosphatase activity in the latter group. Interestingly, systemic OPG treatment prevented joint damage induced by local AdIL-17 gene transfer in type II collagen-immunized mice. These findings suggest T cell IL-17 to be an important inducer of RANKL expression leading to loss of the RANKL/OPG balance, stimulating osteoclastogenesis and bone erosion in arthritis.
authors.affiliation: Rheumatology and Advanced Therapeutics, University Medical Center Nijmegen, Nijmegen, The Netherlands. E.Lubberts@reuma.umcn.nl
authors.forename: Erik
authors.initials: E
authors.lastname: Lubberts
authors.forename: Liduine
authors.initials: L
authors.lastname: van den Bersselaar
authors.forename: Birgitte
authors.initials: B
authors.lastname: Oppers-Walgreen
authors.forename: Paul
authors.initials: P
authors.lastname: Schwarzenberger
authors.forename: Christina J J
authors.initials: CJ
authors.lastname: Coenen-de Roo
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D001842:Bone and Bones / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000378:metabolism*; D002417:Cattle; D003094:Collagen / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay / Q000706:statistics & numerical data; D005786:Gene Expression Regulation / Q000276:immunology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006023:Glycoproteins / Q000096:biosynthesis / Q000378:metabolism* / Q000627:therapeutic use; D006801:Humans; D007274:Injections, Intraperitoneal; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D008811:Mice, Inbred DBA; D010010:Osteoclasts / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000378:metabolism* / Q000627:therapeutic use; D018124:Receptors, Tumor Necrosis Factor; D012995:Solubility; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D020381:Interleukin-17; D008024:Ligands; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D003094:Collagen