@article{cb89ffd4166847f191740e0be42b30d4,
title = "Therapeutic glucocorticoids prevent bone loss but drive muscle wasting when administered in chronic polyarthritis",
abstract = "BackgroundPatients with rheumatoid arthritis (RA) experience extra-articular manifestations including osteoporosis and muscle wasting, which closely associate with severity of disease. Whilst therapeutic glucocorticoids (GCs) reduce inflammation in RA, their actions on muscle and bone metabolism in the context of chronic inflammation remain unclear. We utilised the TNF-tg model of chronic polyarthritis to ascertain the impact of therapeutic GCs on bone and muscle homeostasis in the context of systemic inflammation.MethodsTNF-tg and wild-type (WT) animals received either vehicle or the GC corticosterone (100 mu g/ml) in drinking water at onset of arthritis. Arthritis severity and clinical parameters were measured, serum collected for ELISA and muscle and bone biopsies collected for mu CT, histology and mRNA analysis. In vivo findings were examined in primary cultures of osteoblasts, osteoclasts and myotubes.ResultsTNF-tg mice receiving GCs showed protection from inflammatory bone loss, characterised by a reduction in serum markers of bone resorption, osteoclast numbers and osteoclast activity. In contrast, muscle wasting was markedly increased in WT and TNF-tg animals receiving GCs, independently of inflammation. This was characterised by a reduction in muscle weight and fibre size, and an induction in anti-anabolic and catabolic signalling.ConclusionsThis study demonstrates that when given in early onset chronic polyarthritis, oral GCs partially protect against inflammatory bone loss, but induce marked muscle wasting. These results suggest that in patients with inflammatory arthritis receiving GCs, the development of interventions to manage deleterious side effects in muscle should be prioritised.",
keywords = "Polyarthritis, Glucocorticoids, Muscle wasting, Osteoporosis, TUMOR-NECROSIS-FACTOR, RHEUMATOID-ARTHRITIS, MINERAL DENSITY, VERTEBRAL DEFORMITIES, KAPPA-B, RISK, RECOMMENDATIONS, OSTEOPOROSIS, PREVALENCE, FRACTURES",
author = "Fenton, {C. G.} and Webster, {J. M.} and Martin, {C. S.} and S. Fareed and C. Wehmeyer and H. Mackie and R. Jones and Seabright, {A. P.} and Lewis, {J. W.} and Lai, {Y. C.} and Goodyear, {C. S.} and Jones, {S. W.} and Cooper, {M. S.} and Lavery, {G. G.} and R. Langen and K. Raza and Hardy, {R. S.}",
note = "Funding Information: Collaboration. This research was supported by the Arthritis Research UK grants (Reference: 19859 & 20843) and Wellcome Trust Senior Fellowship (GGL-104612/Z/14/Z). Funding Information: We would like to thank Professor George Kollias (Hellenic Pasteur Institute, Athens, Greece) for providing the hTNFtg mice, the Biomedical Services Unit (University of Birmingham) for supporting animal experiments and the Department of Musculoskeletal Pathology (Robert Aitken Institute, University of Birmingham) for embedding and cutting tissue for histology. JWL was funded by MRC Arthritis Research UK Centre for Musculoskeletal Ageing Research PhD Studentship (MR/P021220/1). Analysis performed by CJM was supported by the Wellcome Trust MIDAS programme. We would also like to acknowledge the Arthritis Research UK Centre of Excellence for the Pathogenesis of Rheumatoid Arthritis in supporting this work. This research was supported by the Arthritis Research UK Centre of Excellence for the Pathogenesis of Rheumatoid Arthritis and the MRC Arthritis Research UK Centre for Musculoskeletal Ageing Research. Funding Information: We would like to thank Professor George Kollias (Hellenic Pasteur Institute, Athens, Greece) for providing the hTNFtg mice, the Biomedical Services Unit (University of Birmingham) for supporting animal experiments and the Department of Musculoskeletal Pathology (Robert Aitken Institute, University of Birmingham) for embedding and cutting tissue for histology. JWL was funded by MRC Arthritis Research UK Centre for Musculoskeletal Ageing Research PhD Studentship (MR/P021220/1). Analysis performed by CJM was supported by the Wellcome Trust MIDAS programme. We would also like to acknowledge the Arthritis Research UK Centre of Excellence for the Pathogenesis of Rheumatoid Arthritis in supporting this work. This research was supported by the Arthritis Research UK Centre of Excellence for the Pathogenesis of Rheumatoid Arthritis and the MRC Arthritis Research UK Centre for Musculoskeletal Ageing Research. Collaboration. This research was supported by the Arthritis Research UK grants (Reference: 19859 & 20843) and Wellcome Trust Senior Fellowship (GGL-104612/Z/14/Z). Publisher Copyright: {\textcopyright} 2019 The Author(s).",
year = "2019",
month = aug,
day = "1",
doi = "10.1186/s13075-019-1962-3",
language = "English",
volume = "21",
pages = "1--12",
journal = "Arthritis Research & Therapy",
issn = "1478-6354",
publisher = "BioMed Central Ltd",
}