title: SKG arthritis as a model for evaluating therapies in rheumatoid arthritis with special focus on bone changes.
abstract: The aim was to further characterize the SKG model of rheumatoid arthritis (RA) and its potential for studying intervention treatments, with special focus on bone targeting therapies. Three individual studies were conducted, using a total of 71 SKG mice, comparing arthritis induction with mannan versus zymosan A, female versus male mice, and the effect of dexamethasone intervention treatment initiated at different time points after arthritis induction. Hind paws were embedded undecalcified in methyl methacrylate, and sections were stained with Masson-Goldner trichrome. Areal Bone Mineral Density (aBMD) of the femora was determined with pDXA. RNA was extracted from the hind paws followed by the quantification by reverse transcriptase PCR. SKG mice stimulated with mannan presented a higher arthritis score than mice stimulated with zymosan A. Female SKG mice developed a more severe arthritis than male SKG mice. Dexamethasone inhibited arthritis clinically as well as histologically when the treatment was initiated prophylactically or within the first week of arthritis. Femoral aBMD was lower in animals with arthritis than in control animals. The RANKL RNA expression was elevated in arthritic mice, whereas OPG RNA expression was unchanged. The results suggest mannan as arthritis inductor and female instead of male mice in experiments as well as an optimal time window for the initiation of treatment. Systemic bone loss as well as local up regulation of RANKL was present early in SKG arthritis. These results demonstrate that SKG arthritis is a suitable new model for evaluating therapies in RA.
authors.affiliation: Department of Rheumatology, Aarhus University Hospital, Nørrebrogade 44, 8000 Aarhus C, Denmark. kresten@ana.au.dk
authors.forename: Kresten Krarup
authors.initials: KK
authors.lastname: Keller
authors.forename: Lisa Mejlvang
authors.initials: LM
authors.lastname: Lindgaard
authors.forename: Lise
authors.initials: L
authors.lastname: Wogensen
authors.forename: Frederik
authors.initials: F
authors.lastname: Dagnæs-Hansen
authors.forename: Jesper Skovhus
authors.initials: JS
authors.lastname: Thomsen
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
authors.forename: Kristian
authors.initials: K
authors.lastname: Stengaard-Pedersen
authors.forename: Ellen-Margrethe
authors.initials: EM
authors.lastname: Hauge
mesh_terms: D015502:Absorptiometry, Photon; D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects*; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D008351:Mannans; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index; D013997:Time Factors; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics; D015054:Zymosan
chemical_list: D018501:Antirheumatic Agents; D008351:Mannans; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D003907:Dexamethasone; D015054:Zymosan; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse