Background Large clinical studies have demonstrated that TNF blockade delays radiological progression in rheumatoid arthritis (RA) independent of the clinical response.
Objectives We aimed to investigate the mechanisms by which adalimumab, a human anti TNF antibody, affects osteoclastogenesis in vivo and in vitro.
Methods Expression of OPG, RANK and RANKL was evaluated by immunohistochemistry and semi quantitative double blind analysis of serial synovial biopsies obtained from 12 RA patients treated with adalimumab before and 8 weeks after treatment initiation. The in-vitro effect of adalimumab on RANKL and OPG expression in osteoblast-like cells with or without TNF priming was evaluated by RT-PCR and Western blots. Further investigation of the direct effect of adalimumab on osteoclasts formation (TRAP staining) and function was tested in a bone resorption assay using blood derived CD14 positive monocytes. Resorption area and number of pits were analysed by computer assisted image analysis.
Results Treatment with adalimumab significantly decreased the RANKL/OPG ratio and RANK expression in synovial tissue in parallel with a reduction in the number of synovial macrophages, while no changes were seen in the number of synovial lymphocytes. No significant differences were observed between EULAR responders and non-responders. In-vitro adalimumab mimicked the in-vivo effect inducing a decrease in the RANKL/OPG ratio in osteoblast-like cells (SaOS2). In addition adalimumab was able to inhibit in-vitro osteoclast formation and bone resorption even in the presence of RANKL.
Conclusions Therapy with adalimumab regulates not only synovial inflammation but also bone metabolism through direct modulation of the RANKL/RANK/OPG pathway and inhibition of osteoclasts formation. These effects might explain the bone sparing effect seen with TNF blockade even in the presence of ongoing inflammation.
Disclosure of Interest A. Krishnamurthy: None Declared, S. Revu: None Declared, P. Neregård: None Declared, A. Hensvold: None Declared, M. Engström: None Declared, E. Erik af Klint: None Declared, D. Makrygiannakis: None Declared, A. Catrina Grant/Research support from: AI Catrina has received an unrestricted research grant from Abbott.
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