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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenoviruses, Human / genetics
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Adenoviruses, Human / immunology
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Animals
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Arthritis, Experimental / immunology*
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Arthritis, Experimental / metabolism
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Arthritis, Experimental / pathology*
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Arthritis, Experimental / prevention & control
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Bone and Bones / immunology
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Bone and Bones / metabolism
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Bone and Bones / pathology*
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Carrier Proteins / biosynthesis
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Carrier Proteins / metabolism*
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Cattle
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Collagen / immunology*
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Enzyme-Linked Immunosorbent Assay / statistics & numerical data
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Gene Expression Regulation / immunology
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Gene Transfer Techniques
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Genetic Vectors
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Glycoproteins / biosynthesis
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Glycoproteins / metabolism*
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Glycoproteins / therapeutic use
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Humans
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Injections, Intraperitoneal
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Interleukin-17 / antagonists & inhibitors
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Interleukin-17 / biosynthesis
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Interleukin-17 / genetics
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Interleukin-17 / physiology*
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Ligands
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Male
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Membrane Glycoproteins / biosynthesis
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Membrane Glycoproteins / metabolism*
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Mice
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Mice, Inbred DBA
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Osteoclasts / immunology
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Osteoclasts / metabolism
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Osteoclasts / pathology
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Osteoprotegerin
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Cytoplasmic and Nuclear / biosynthesis
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Receptors, Cytoplasmic and Nuclear / therapeutic use
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Receptors, Tumor Necrosis Factor
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Solubility
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Synovial Membrane / immunology
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Synovial Membrane / metabolism
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Synovial Membrane / pathology
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Up-Regulation / genetics
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Up-Regulation / immunology
Substances
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Carrier Proteins
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Glycoproteins
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Interleukin-17
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Ligands
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Membrane Glycoproteins
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Osteoprotegerin
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Cytoplasmic and Nuclear
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Receptors, Tumor Necrosis Factor
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TNFRSF11A protein, human
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TNFRSF11B protein, human
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TNFSF11 protein, human
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Tnfrsf11a protein, mouse
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Tnfrsf11b protein, mouse
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Tnfsf11 protein, mouse
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Collagen