Decrease of CD68 Synovial Macrophages in Celastrol Treated Arthritic Rats.

Rita Cascão,Bruno Vidal,Eunice Paisana,Inês P Lopes,José Rino,Luis F Moita,João E Fonseca

doi:10.1371/journal.pone.0142448

Rita Cascão, Bruno Vidal + Show 5 more

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https://doi.org/10.1371/journal.pone.0142448

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Abstract

BackgroundRheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease characterized by cellular infiltration into the joints, hyperproliferation of synovial cells and bone damage. Available treatments for RA only induce remission in around 30% of the patients, have important adverse effects and its use is limited by their high cost. Therefore, compounds that can control arthritis, with an acceptable safety profile and low production costs are still an unmet need. We have shown, in vitro, that celastrol inhibits both IL-1β and TNF, which play an important role in RA, and, in vivo, that celastrol has significant anti-inflammatory properties. Our main goal in this work was to test the effect of celastrol in the number of sublining CD68 macrophages (a biomarker of therapeutic response for novel RA treatments) and on the overall synovial tissue cellularity and joint structure in the adjuvant-induced rat model of arthritis (AIA).MethodsCelastrol was administered to AIA rats both in the early (4 days after disease induction) and late (11 days after disease induction) phases of arthritis development. The inflammatory score, ankle perimeter and body weight were evaluated during treatment period. Rats were sacrificed after 22 days of disease progression and blood, internal organs and paw samples were collected for toxicological blood parameters and serum proinflammatory cytokine quantification, as well as histopathological and immunohistochemical evaluation, respectively.ResultsHere we report that celastrol significantly decreases the number of sublining CD68 macrophages and the overall synovial inflammatory cellularity, and halted joint destruction without side effects.ConclusionsOur results validate celastrol as a promising compound for the treatment of arthritis.

Highlights

Rheumatoid arthritis (RA) is a chronic immune mediated inflammatory disease that is mainly characterized by hyperproliferation of synovial cells, infiltration of mononuclear cells into the synovium and early destruction of articular cartilage and bone, causing progressive damage to the musculoskeletal system and the loss of physical function and life quality [1,2,3]
We report that celastrol significantly decreases the number of sublining CD68 macrophages and the overall synovial inflammatory cellularity, and halted joint destruction without side effects
Drugs used to treat RA, ranging from nonsteroidal anti-inflammatory drugs (NSAIDs) to diseasemodifying antirheumatic drugs (DMARDs), and biological DMARDs, still cause severe side effects [15, 16] and are only able to induce remission in around 20–30% of the patients, leaving the majority of the individuals affected by RA with a chronic inflammatory process that will lead to damage

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic immune mediated inflammatory disease that is mainly characterized by hyperproliferation of synovial cells, infiltration of mononuclear cells into the synovium and early destruction of articular cartilage and bone, causing progressive damage to the musculoskeletal system and the loss of physical function and life quality [1,2,3]. Activated synovial fibroblasts, chondrocytes and osteoclasts contribute to the underlying cartilage and bone damage [11] Despite this clear link between inflammation and increased bone turnover in RA and the existence of several therapeutical options, their efficacy on inflammation and bone treatment seem to be uncoupled, with some drugs suppressing inflammation but failing to protect bone [12, 13] and others halting bone destruction but with no effect on controlling inflammation [14]. Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease characterized by cellular infiltration into the joints, hyperproliferation of synovial cells and bone damage. Our main goal in this work was to test the effect of celastrol in the number of sublining CD68 macrophages (a biomarker of therapeutic response for novel RA treatments) and on the overall synovial tissue cellularity and joint structure in the adjuvant-induced rat model of arthritis (AIA)

Methods

Results

Conclusion