The X-Linked Inhibitor of Apoptosis Protein Inhibitor Embelin Suppresses Inflammation and Bone Erosion in Collagen Antibody Induced Arthritis Mice.

Anak A S S K Dharmapatni,Malcolm D Smith,Tania N Crotti,Egon Perilli,Melissa D Cantley,David R Haynes,Victor Marino

doi:10.1155/2015/564042

Anak A S S K Dharmapatni, Malcolm D Smith + Show 5 more

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https://doi.org/10.1155/2015/564042

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Abstract

Objective. To investigate the effect of Embelin, an inhibitor of X-Linked Inhibitor of Apoptosis Protein (XIAP), on inflammation and bone erosion in a collagen antibody induced arthritis (CAIA) in mice. Methods. Four groups of mice (n = 6 per group) were allocated: CAIA untreated mice, CAIA treated with Prednisolone (10 mg/kg/day), CAIA treated with low dose Embelin (30 mg/kg/day), and CAIA treated with high dose Embelin (50 mg/kg/day). Joint inflammation was evaluated using clinical paw score and histological assessments. Bone erosion was assessed using micro-CT, tartrate resistant acid phosphatase (TRAP) staining, and serum carboxy-terminal collagen crosslinks (CTX-1) ELISA. Immunohistochemistry was used to detect XIAP protein. TUNEL was performed to identify apoptotic cells. Results. Low dose, but not high dose Embelin, suppressed inflammation as reflected by lower paw scores (P < 0.05) and lower histological scores for inflammation. Low dose Embelin reduced serum CTX-1 (P < 0.05) and demonstrated lower histological score and TRAP counting, and slightly higher bone volume as compared to CAIA untreated mice. XIAP expression was not reduced but TUNEL positive cells were more abundant in Embelin treated CAIA mice. Conclusion. Low dose Embelin suppressed inflammation and serum CTX-1 in CAIA mice, indicating a potential use for Embelin to treat pathological bone loss.

Highlights

Rheumatoid arthritis (RA) involves changes in the synovial membrane, including thickening of the synovial lining, persistent infiltration of inflammatory cells, angiogenesis, and production of inflammatory cytokines leading to subsequent cartilage and bone degradation
collagen antibody induced arthritis (CAIA) mice treated with a low dose of Embelin demonstrated markedly lower paw scores throughout the experiment (Figure 1(b)) with statistically significant differences observed on day 6 (P < 0.05)
The mice treated with high dose Embelin demonstrated lower mean paw scores, these were not significant statistically when compared to the CAIA untreated group

Summary

Introduction

Rheumatoid arthritis (RA) involves changes in the synovial membrane, including thickening of the synovial lining, persistent infiltration of inflammatory cells, angiogenesis, and production of inflammatory cytokines leading to subsequent cartilage and bone degradation. The proliferation of synovial cells and the persistence of inflammatory cells in the RA synovium are associated with a marked reduction in apoptosis [2]. Inducing apoptosis by targeting the upstream pathway with anti-death receptor 5 (DR5) [3] and soluble Fas monoclonal antibody [4] was beneficial in an adjuvant induced arthritis rat model and in a severe combined immunodeficient-HuRAg mouse model, respectively. Apoptosis is activated through the extrinsic and/or intrinsic pathways. Both pathways converge downstream at the level of executor caspases such as caspases 3, 6, and 7 [5], which are directly responsible for morphological changes in apoptotic cells. The inhibitory apoptotic proteins family (IAPs) regulate both upstream (caspase-9) and downstream

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