SKG arthritis as a model for evaluating therapies in rheumatoid arthritis with special focus on bone changes
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.
KeywordsRheumatoid arthritis Bone Animal models Experimental arthritis Osteoclast SKG mouse
The authors are grateful for the technical assistance of Dorthe Clausen, Jette Barlach, and Lotte Arentoft. This work was supported by the Danish Rheumatism Association, the Hørslev Foundation, Clinical Institute Aarhus University, Peter Ryholts Grant, the Hede Nielsens Family Foundation, The A. P. Møller Foundation for the Advancement of Medical Science and Aase and Ejnar Danielsens Foundation.
Conflict of interest
The authors declare that they have no conflict of interest.
- 1.Keystone EC, Kavanaugh AF, Sharp JT, Tannenbaum H, Hua Y et al (2004) Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum 50(5):1400–1411PubMedCrossRefGoogle Scholar
- 2.Graudal N, Jurgens G (2010) Similar effects of disease-modifying antirheumatic drugs, glucocorticoids, and biologic agents on radiographic progression in rheumatoid arthritis: meta-analysis of 70 randomized placebo-controlled or drug-controlled studies, including 112 comparisons. Arthritis Rheum 62(10):2852–2863PubMedCrossRefGoogle Scholar
- 20.Hetland ML, Stengaard-Pedersen K, Junker P, Lottenburger T, Ellingsen T et al (2006) Combination treatment with methotrexate, cyclosporine, and intraarticular betamethasone compared with methotrexate and intraarticular betamethasone in early active rheumatoid arthritis: an investigator-initiated, multicenter, randomized, double-blind, parallel-group, placebo-controlled study. Arthritis Rheum 54(5):1401–1409PubMedCrossRefGoogle Scholar