Dr. Yannaki and Ms Papadopoulou contributed equally to this work.
The proteasome inhibitor bortezomib drastically affects inflammation and bone disease in adjuvant-induced arthritis in rats
Article first published online: 29 OCT 2010
Copyright © 2010 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 62, Issue 11, pages 3277–3288, November 2010
How to Cite
Yannaki, E., Papadopoulou, A., Athanasiou, E., Kaloyannidis, P., Paraskeva, A., Bougiouklis, D., Palladas, P., Yiangou, M. and Anagnostopoulos, A. (2010), The proteasome inhibitor bortezomib drastically affects inflammation and bone disease in adjuvant-induced arthritis in rats. Arthritis & Rheumatism, 62: 3277–3288. doi: 10.1002/art.27690
- Issue published online: 29 OCT 2010
- Article first published online: 29 OCT 2010
- Accepted manuscript online: 18 AUG 2010 12:00AM EST
- Manuscript Accepted: 27 JUL 2010
- Manuscript Received: 26 JUN 2009
- Aristotle University and George Papanicolaou Hospital
To explore the effect of bortezomib in splenocytes and fibroblast-like synoviocytes (FLS) and its in vivo potency in a rat model of adjuvant-induced arthritis (AIA), which resembles human rheumatoid arthritis (RA).
AIA was induced with Freund's complete adjuvant. Splenocyte and FLS proliferation and apoptosis were measured by radioactivity incorporation and flow cytometry, respectively. The invasiveness of FLS from rats with AIA was tested in a Transwell system. The pattern of cytokine secretion was evaluated by cytometric bead array in splenocyte supernatants. Bortezomib was administered prophylactically or therapeutically, and arthritis was assessed clinically and histologically. Immunohistochemistry was performed for markers of inflammation and angiogenesis in joints. Hematologic and biochemical parameters were tested in peripheral blood (PB). Representative animals were examined by computed tomography (CT) scanning before and after bortezomib administration. The expression of Toll-like receptor 2 (TLR-2), TLR-3, and TLR-4 in PB and FLS was measured by real-time polymerase chain reaction, and alterations in specific cell populations in PB and spleen were determined by flow cytometry.
In vitro, bortezomib exhibited significant inhibitory and proapoptotic activity in splenocytes and FLS from rats with AIA, altered the inflammatory cytokine pattern, and reduced the invasiveness of FLS from rats with AIA. In vivo, bortezomib significantly ameliorated disease severity. Remission was associated with improved histology and decreased expression of CD3, CD79a, CD11b, cyclooxygenase 1, and factor VIII in target tissues as well as down-regulation of TLR expression in PB and cultured FLS. CT scanning demonstrated a bone healing effect after treatment.
Our findings suggest that bortezomib affects AIA in a pleiotropic manner and that this drug may be effective in RA.