title: Combined treatment with hyaluronan inhibitor Pep-1 and a selective adenosine A2 receptor agonist reduces inflammation in experimental arthritis.
abstract: Investigations have suggested degradation of native hyaluronan (HA) into small oligosaccharides as being involved in the development and progression of inflammatory diseases, particularly rheumatoid arthritis (RA). Inflammatory responses occur by modulating the TLR4 and 2, and the CD44 natural HA receptor. As reported recently, the adenosine A2 receptor (A2AR) plays an important anti-inflammatory role in arthritis. TLR4, TLR2 and CD44 stimulation activate NF-κB, which stimulates the production of pro-inflammatory cytokines and other mediators. In contrast, A2AR stimulation inhibits NF-κB activation. The aim of this study was to investigate the effect of combined treatment of HA inhibitor Pep-1 and a selective A2AR agonist (CV-1808) in collagen-induced arthritis (CIA) in mice. Arthritis was induced via intradermal injection of bovine collagen-II. Mice were treated with Pep-1 plus CV-1808 intraperitoneally daily for 20 d. CIA increased TLR4, TLR2, CD44 and A2AR mRNA expression and the related proteins in the joint cartilage of arthritic mice, where significantly increased concentrations were of TNF-α, IL-1-β, IL-17, matrix metalloprotease-13 and inducible nitric oxide synthase. Pep-1 with CV-1808 treatment significantly reduced CIA damage and all the up-regulated biochemical parameters. These reductions were supported by microscopic analysis and synovial fluid HA levels.
authors.affiliation: Department of Biomedical Sciences and Morphological and Functional Images, School of Medicine, University of Messina, Messina, Italy.
authors.forename: Giuseppe M
authors.initials: GM
authors.lastname: Campo
authors.forename: Angela
authors.initials: A
authors.lastname: Avenoso
authors.forename: Angela
authors.initials: A
authors.lastname: D'Ascola
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Nastasi
authors.forename: Antonio
authors.initials: A
authors.lastname: Micali
authors.forename: Domenico
authors.initials: D
authors.lastname: Puzzolo
authors.forename: Antonina
authors.initials: A
authors.lastname: Pisani
authors.forename: Vera
authors.initials: V
authors.lastname: Prestipino
authors.forename: Michele
authors.initials: M
authors.lastname: Scuruchi
authors.forename: Alberto
authors.initials: A
authors.lastname: Calatroni
authors.forename: Salvatore
authors.initials: S
authors.lastname: Campo
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D006820:Hyaluronic Acid / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007596:Joints / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D023421:Models, Animal; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage* / Q000494:pharmacology; D059748:Proteolysis / Q000187:drug effects; D043704:Receptor, Adenosine A2B / Q000235:genetics / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D016207:Cytokines; D018960:Hyaluronan Receptors; D018836:Inflammation Mediators; D010455:Peptides; D043704:Receptor, Adenosine A2B; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C575521:glycyl-alanyl-histidyl-tryptophyl-glutaminyl-phenylalanyl-asparagyl-alanyl-leucyl-threonyl-valyl-arginine; D006820:Hyaluronic Acid; D052247:Nitric Oxide Synthase Type II; D053509:Matrix Metalloproteinase 13; C026708:2-phenylaminoadenosine; D000241:Adenosine
keywords: CD44; NF-kB; Toll-like receptors; adenosine; arthritis; cytokines; hyaluronan